Novel azole compound

ABSTRACT

Azole compounds represented by formula I: 
     
       
         
         
             
             
         
       
     
     wherein ring A is isoxazole and the like, R1 is a substituted or unsubstituted aryl group and the like, R2 is a hydrogen atom and the like, and R3 is a substituted or unsubstituted alkyl group and the like, and pharmaceutically acceptable salts thereof inhibit the physiological activity of lysophosphatidic acid (LPA), and are useful as for the prophylaxis or treatment of diseases in which inhibition of the physiological activity of LPA is useful for the prophylaxis or treatment thereof, such as diseases involving the LPA receptor.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a continuation of International Patent ApplicationNo. PCT/JP2004/011565, filed on Aug. 5, 2004, and claims priority toJapanese Patent Application No. 2003-287234, filed on Aug. 5, 2003,Japanese Patent Application No. 2004-034300, filed on Feb. 2, 2004, andJapanese Patent Application No. 2004-197389, filed on Jul. 2, 2004, allof which are incorporated herein by reference in their entireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel azole compounds, salts thereof,and uses of such an azole compound as a pharmaceutical product. Thecompounds of the present invention inhibit the physiological activity oflysophosphatidic acid (LPA), and therefore, are useful as agents for theprophylaxis or treatment of diseases in which inhibition of thephysiological activity of LPA is useful for the prophylaxis or treatmentthereof, such as diseases in which LDA receptor participates. Morespecifically, the compounds are useful as agents for the prophylaxis ortreatment of fibrosis of organs (liver, kidney, lung, and the like),liver diseases (acute or chronic hepatitis, liver fibrosis, livercirrhosis, portal hypertension, regenerative failure, non-alcoholicsteatohepatitis (NASH), liver hypofunction, hepatic blood flow disorder,and the like), cell proliferative disease (cancer (solid tumor, solidtumor metastasis, vascular fibroma, myeloma, multiple myeloma, Kaposi'ssarcoma, leukemia, and the like) and invasive metastasis of cancer cell,and the like), inflammatory disease (psoriasis, nephropathy, pneumoniaand the like), gastrointestinal tract disease (irritable bowel syndrome(IBS), inflammatory bowel disease (IBD), abnormal pancreatic secretion,and the like), renal disease, urinary tract-associated disease (benignprostatic hyperplasia or symptoms associated with neuropathic bladderdisease, spinal cord tumor, hernia of intervertebral disk, spinal canalstenosis, symptoms derived from diabetes, lower urinary tract disease(obstruction of lower urinary tract, and the like), inflammatory diseaseof lower urinary tract, dysuria, frequent urination, and the like),pancreas disease, abnormal angiogenesis-associated disease (arterialobstruction and the like), brain-associated disease (cerebralinfarction, cerebral hemorrhage, and the like), peripheral neuropathy,and the like. Particularly, the present compounds are useful as agentsfor the prophylaxis or treatment of fibrosis of organs (liver, kidney,lung, and the like) or liver diseases.

2. Discussion of the Background

Lysophosphatidic acid (LPA) exists in a trace amount in livingorganisms, and is a lysophospholipid that shows various physiologicalactivities. LPA is produced and released from various cells stimulatedby a physiologically active substance (The Journal of BiologicalChemistry, (US), 1995, vol. 270, pp. 12949-12952 and The Journal ofBiological Chemistry, (US), 1992, vol. 267, pp. 10988-10993). Since itis present in a small amount in plasma and in an abundant amount inserum in living organisms, the major site (cell) of production isconsidered to be platelets (The Biochemical Journal, (UK), 1993, vol.291, pp. 677-680). Thus, LPA concentration is considered to increase inthe topical site of inflammation or hemorrhage. In fact, it has beenreported that LPA concentration increases in human arteriosclerosislesion and in brain spinal fluid in intracerebral hemorrhage model(Proceedings of the National Academy of Sciences USA, (US), 1999, vol.96, pp. 6931-6936 and Journal of Neurochemistry, (UK), 1996, vol. 67,pp. 2300-2305). Moreover, activation of platelets has been reported inacute or chronic hepatitis patients (The Tokai Journal of Experimentaland Clinical Medicine, (JP), 2002, vol. 27, pp. 101-106,Hepato-Gastroenterology, (GK) 2001, vol. 48, pp. 818-822, and Journal ofInvestigative Medicine, (US), 2001, vol. 49, pp. 407-412), and anincrease in the LPA concentration at a blood or liver topical site issuggested in both acute and chronic hepatitis patients. In addition,there is a report on an increased LPA concentration in ascites ofintraperitoneal disseminated ovarian cancer patients and in the blood ofmultiple myeloma patients (Gynecologic Oncology, (US), 1998, vol. 71,pp. 364-368 and Lipids, (US). 1999, vol. 34, pp. 17-21).

It is being elucidated that LPA functions as an intercellular messengerthat extracellularly acts via a cell surface receptor. The genes of thereceptor, G-protein-coupled receptor, EDG2 (endothelial differentiationgene 2) (a.k.a. 1pA1 (Lysophophatidic acid receptor 1) or VZG-1)(Biochemical and Biophysical Research Communications, (US), 1997, vol.231, pp. 619-622), EDG4 (a.k.a. 1pA2 (lysophophatidic acid receptor 2))and EDG7 (a.k.a. 1pA3 (lysophophatidic acid receptor 3)) gene have beencloned to the present date (Molecular Pharmacology, (US), 2000, vol. 58,pp. 1188-1196), and they have been reported to be LPA specific receptors(FEBS Letters, (DE) 2000, vol. 478, pp. 159-165 and Prostaglandins &other Lipid Mediators (US), 2001, vol. 64, pp. 21-32).

As the physiological activity of LPA, for example, cell growth promotingaction, enhancing action on chemotactic and infiltrating activities,platelet aggregation action, action of cell contraction and the like areknown, and LPA is particularly useful for the organs shown below,particularly for the disease/symptoms in organ shown below.

LPA has been reported to promote growth of stellate cell in the liver(Biochemical and Biophysical Research Communications, (US), 2000, vol.248, pp. 436-440). LPA has also been reported to cause contraction ofcultured activated stellate cells (Biochemical and Biophysical ResearchCommunications, (US), 2000, vol. 277, pp. 72-78). When the contractingfunction of stellate cells is promoted by liver injury, it is consideredthat hepatic sinusoid microcirculation is impaired, the blood streaminto the liver is prevented, causing portal hypertension and furtheresophageal varices (Seminars in Liver Disease, (US), 2001, vol. 21, pp.337-349 and Gut, (UK), 2002, vol. 50, pp. 571-581). LPA has also beenreported to induce chemotaxis of stellate cells (Journal of BiomedicalScience, (CH), 2003, vol. 10, pp. 352-358). On the other hand, LPA hasbeen reported to inhibit the growth of parenchymal cells stimulated byHGF (hepatic growth factor) (Biochemical and Biophysical ResearchCommunications, (US), 2000, vol. 248, pp. 436-440).

As one of the pharmacological activities induced by LPA, the contractingphenomenon of rat colon and guinea pig ileum has been reported (Journalof Pharmacy and Pharmacology, (UK) 1982, vol. 34, pp. 514-516 andJournal of Pharmacy and Pharmacology, (UK), 1991, vol. 43, pp. 774-778).In recent years, it has been shown that LPA promotes the contraction ofileum, as do acetylcholine and high K⁺ (Canadian journal of physiologyand pharmacology, (CA), 2000, vol. 78, pp. 729-736).

With regard to pancreas, it has been described that LPA receptorantagonist has a decreasing action of pancreatic secretion(WO03/007991).

LPA has been reported to promote growth of vascular smooth muscle cell.WO01/060819 describes that the compound of Example 115 (methyl3-([4-[4-([[1-(2-chlorophenyl)ethoxy]carbonyl]amino)-3-methyl-5-isoxazolyl]benzyl]-sulfanyl)propanoate)had a strong EDG2 antagonistic action and exhibited an improving actionin peripheral circulation disorder model induced by lactic acid, whichis an animal model of peripheral arterial obstruction.

There are reports that LPA has a contracting action on bladder smoothmuscle cell isolated from bladder (The Journal of urology, (US), 1999,vol. 162, pp. 1779-1784), and promotes growth of prostate-derivedepithelial cell (The Journal of urology, (US), 2000, vol. 163, pp.1027-1032). In addition, WO02/062389 shows that LPA contracts theurinary tract and prostate in vitro and increases intraurethral pressurein vivo.

In addition, there is a report on the finding that, by LPA acting on aprostatic interstitial cell which expresses LPA receptor, theinterstitial cell is grown and that the growth of the interstitial cellresults in the progression of prostate hyperplasia (WO03/013605).

There are many reports on the involvement of LPA in the growth of cellsresponsible for the fibrosis of organs represented by fibroblasts invarious organs. For example, smooth muscle cells (The American journalof physiology, (US), 1994, vol. 267, pp. C204-C210 and Atherosclerosis,(IE), 1997, vol. 130, pp. 121-131), renal mesangial cells (Clinicalscience, (UK), 1999, vol. 96, pp. 431-436), hepatic stellate cells(Biochemical and Biophysical Research Communications, (US), 2000, vol.248, pp. 436-440), lung fibroblast (The Journal of Pharmacology andExperimental Therapeutics, (US). 2000, vol. 294, pp. 1076-1982),fibroblast (Naunyn-Schmiedeberg's archives of pharmacology, (DE), 1997,vol. 355, pp. 1-7) and the like can be mentioned. In general, whenfibroblasts is proliferated, it is considered production of collagen ispromoted, and also fibrosis of organs is considered to be promoted.Therefore, an LPA receptor antagonist is useful for the treatment orprophylaxis of fibrosis in various organs.

LPA promotes the growth of various cancer cells and is suggested to berelated not only to diseases but also to infiltration and metastasis ofcancer, because a promoting action of cancer cell infiltration and thelike are observed (Biochemical and Biophysical Research Communications,(US), 1993, vol. 193, pp. 497-503).

LPA has been reported to promote the chemotactic ability of humanmonocytes (The Journal of Biological Chemistry, (US), 1995, vol. 270,pp. 25549-25556), and be involved in the growth and infiltration of Tcells (Biochimica et Biophysica Acta, (DE), 2002, vol. 1582, pp.168-174).

LPA has also been reported to cause neurite retraction and cell death innerve cells, and is particularly suggested to be possibly involved inthe injury of nerve cells during bleeding (Journal of Neurochemistry,(UK), 1993, vol. 61, pp. 340-343 and Journal of Neurochemistry, (UK),1998, vol. 70, pp. 66-76).

A pharmaceutical agent that inhibits the above-mentioned physiologicalactivities of LPA is considered to lead to the prophylaxis or treatmentof fibrosis of organs (liver, kidney, lung, and the like), hepaticdisease (acute or chronic hepatitis, liver fibrosis, liver cirrhosis,portal hypertension, regenerative failure, non-alcoholic steatohepatitis(NASH), liver hypofunction, hepatic blood flow disorder, and the like),cell proliferative disease (cancer (solid tumor, solid tumor metastasis,vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia,and the like) and invasive metastasis of cancer cell and the like),inflammatory disease (psoriasis, nephropathy, pneumonia, and the like),gastrointestinal tract disease (irritable bowel syndrome (MS),inflammatory bowel disease (IBD), abnormal pancreatic secretion, and thelike), renal disease, urinary tract-associated disease (benign prostatichyperplasia or symptoms associated with neuropathic bladder disease,spinal cord tumor, hernia of intervertebral disk, spinal canal stenosis,symptoms derived from diabetes, lower urinary tract disease (obstructionof lower urinary tract and the like), inflammatory disease of lowerurinary tract, dysuria, frequent urination, and the like), pancreasdisease, abnormal angiogenesis-associated disease (arterial obstructionand the like), brain-associated disease (cerebral infarction, cerebralhemorrhage, and the like), peripheral neuropathy, and the like.

As a compound having an azole skeleton as in the present invention, forexample, WO01/060819 discloses isoxazole compounds and isothiazolecompounds represented by the following formulas, which have an LPAreceptor antagonistic action. However, WO01/060819 does not disclosecompounds in which either R1 or R2 is a hydrogen atom.

-   -   X═O,S    -   R1=alkyl group, aryl group, heterocyclic group, alkyloxy group,        aryloxy group, alkylthio group, arylthio group, each of which        optionally having substituent(s), or halogen atom    -   R2=alkyl group, aryl group, heterocyclic group, alkyloxy group,        aryloxy group, each of which optionally having substituent(s),        or halogen atom

In addition, a production method of the isothiazole compound of thefollowing formula has been reported (Journal of Heterocyclic Chemistry,(US), 1977, vol. 14, pp. 725), but its biological activity has not beendescribed at all.

In addition, several production methods of compounds having a diazoleskeleton as in the present invention have been reported.

For example, EP-A-0120821 discloses oxadiazole compounds of thefollowing formula as a herbicide, but the pharmaceutical use of such acompound is not described at all in EP-A-0120821.

As for such oxadiazole compounds, other references (Journal of theChemical Society. Perkin Transactions 2, (UK), 1992, p. 1643, Farmaco,Edizione Scientifica, (IT), 1971, vol. 26, p. 241, etc.) reportproduction methods thereof and the like, but do not describe theirbiological activities at all.

Furthermore, ZA-6800779 describes an oxadiazole compound of thefollowing formula as one of the compounds having a central nervoussystem suppressing action, an anti-convulsion action, and a musclerelaxation action, but does not describe activity for any disease basedon inhibition of the physiological activity of LPA as described in thepresent specification.

While a production method of N-oxy-oxadiazole compounds of the followingformula has been reported (Journal of Heterocyclic Chemistry, (US),1972, vol. 9, p. 837 and Journal of the Chemical Society. PerkinTransactions 2, (UK), 1973, p. 1613), its biological activity has notbeen described at all.

While a production method of thiadiazole compounds of the followingformula has been reported (Journal of the Chemical Society), (UK), 1965,p. 5166), its biological activity has not been described at all.

While a production method of thiadiazole compounds of the followingformula has been described (Chemical and Pharmaceutical Bulletin (UK),1981, vol. 29, p. 1743), its biological activity has not been describedat all.

SUMMARY OF THE INVENTION

Accordingly, it is one object of the present invention to provide novelcompounds which are pharmaceutically active.

It is another object of the present invention to provide novel compoundswhich inhibit the physiological activity of LPA (hereinafter to besimply referred to as LPA inhibitory action).

It is another object of the present invention to provide novel methodsfor making such compounds.

It is another object of the present invention to provide novelpharmaceutical compositions which contain such a compound.

It is another object of the present invention to provide novel methodsof using such a compound.

It is another object of the present invention to provide novel methodsof using such a pharmaceutical composition.

It is another object of the present invention to provide novel methodsfor the prophylaxis or treatment of fibrosis of organs (liver, kidney,lung, and the like), hepatic disease (acute or chronic hepatitis, liverfibrosis, liver cirrhosis, portal hypertension, regenerative failure,non-alcoholic steatohepatitis (NASH), liver hypofunction, hepatic bloodflow disorder, and the like), cell proliferative disease (cancer (solidtumor, solid tumor metastasis, vascular fibroma, myeloma, multiplemyeloma, Kaposi's sarcoma, leukemia, and the like) and invasivemetastasis of cancer cell and the like), inflammatory disease(psoriasis, nephropathy, pneumonia, and the like), gastrointestinaltract disease (irritable bowel syndrome (EBS), inflammatory boweldisease (IBD), abnormal pancreatic secretion, and the like), renaldisease, urinary tract-associated disease (benign prostatic hyperplasiaor symptoms associated with neuropathic bladder disease, spinal cordtumor, hernia of intervertebral disk, spinal canal stenosis, symptomsderived from diabetes, lower urinary tract disease (obstruction of lowerurinary tract and the like), inflammatory disease of lower urinarytract, dysuria, frequent urination, and the like), pancreas disease,abnormal angiogenesis-associated disease (arterial obstruction and thelike), brain-associated disease (cerebral infarction, cerebralhemorrhage, and the like), peripheral neuropathy, and the like by theuse of such a compound or such a pharmaceutical composition.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' synthesizingof various azole compounds and the examination of the inhibitoryactivity thereof using the evaluation system (evaluation system ofintracellular Ca²⁺ concentration increasing action by LPA) described inthis specification. As a result, we have surprisingly found that suchcompounds show a strong inhibitory activity.

Accordingly, the present invention provides the following:

(1) An azole compound represented by the following formula I:

whereinring A is

R1 is any of a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstitutedcycloalkenyl group, a substituted or unsubstituted aryl group, asubstituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, a halogen atom, a substituted orunsubstituted alkoxy group, a substituted or unsubstituted aryloxygroup, a substituted or unsubstituted heteroaryloxy group, a substitutedor unsubstituted alkylthio group, a substituted or unsubstitutedarylthio group, a substituted or unsubstituted heteroarylthio group, asubstituted or unsubstituted alkylamino group, a substituted orunsubstituted dialkylamino group, a substituted or unsubstitutedcycloalkylamino group, a substituted or unsubstituted dicycloalkylaminogroup, a substituted or unsubstituted arylamino group, a substituted orunsubstituted heteroarylamino group, a substituted or unsubstitutedalkanoyl group, a substituted or unsubstituted carboxylic acid estergroup, a substituted or unsubstituted carbamoyl group, and an aminogroup optionally substituted by amino-protecting group(s);

R2 is any of a hydrogen atom, a substituted or unsubstituted lower alkylgroup, a substituted or unsubstituted aralkyl group, a substituted orunsubstituted aryl group, a substituted or unsubstituted heteroarylgroup, and a hydroxyl group; and

R3 is any of a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, and a group represented by thefollowing formula II:

-   -   wherein

R4 is any of a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstitutedcycloalkenyl group, a substituted or unsubstituted aryl group, asubstituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, a halogen atom, a substituted orunsubstituted alkoxy group, a substituted or unsubstituted aryloxygroup, a substituted or unsubstituted heteroaryloxy group, a substitutedor unsubstituted alkylthio group, a substituted or unsubstitutedarylthio group, a substituted or unsubstituted heteroarylthio group, asubstituted or unsubstituted alkylamino group, a substituted orunsubstituted dialkylamino group, a substituted or unsubstitutedcycloalkylamino group, a substituted or unsubstituted dicycloalkylaminogroup, a substituted or unsubstituted arylamino group, a substituted orunsubstituted heteroarylamino group, and an amino group optionallysubstituted by amino-protecting group(s); and

R5 and R6 may be the same or different and each is any of a hydrogenatom, a substituted or unsubstituted lower alkyl group, a substituted orunsubstituted aryl group, a substituted or unsubstituted heteroarylgroup, a substituted or unsubstituted heterocyclic group, and asubstituted or unsubstituted aralkyl group, or R5 and R6 optionallyform, together with the carbon atom bonded thereto, a 3- to 8-memberedring,

provided that the following (i) to (viii) are excluded:

(i) a compound wherein ring A is ring-4, R1 is a normal propoxy group,R2 is a hydrogen atom, and R3 is a isopropyl group;

(ii) a compound wherein ring A is ring-6, and R1 is a methyl group;

(iii) a compound wherein ring A is ring-(, R1 is a phenyl group, R2 is ahydrogen atom, and R3 is an ethyl group;

(iv) a compound wherein ring A is ring-6, R1 is am-trifluoromethylphenyl group, and R2 is a hydrogen atom, R3 is an ethylgroup;

(v) a compound wherein ring A is ring-7, and R1 is a methyl group;

(vi) a compound wherein ring A is ring-8, and R1 is a methyl group;

(vii) a compound wherein ring A is ring-9, and R1 is a methyl group, R2is a hydrogen atom, and R3 is an ethyl group or a benzyl group; and

(viii) a compound wherein ring A is ring-9, R1 is a phenyl group, R2 isa hydrogen atom or a methyl group, and R3 is an ethyl group,

or a pharmaceutically acceptable salt thereof.

(2) The azole compound of the above-mentioned (1), wherein, in formulaI,

R1 is any of a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, a halogen atom, a substituted orunsubstituted alkoxy group, a substituted or unsubstituted aryloxygroup, a substituted or unsubstituted heteroaryloxy group, a substitutedor unsubstituted alkylthio group, a substituted or unsubstitutedarylthio group, a substituted or unsubstituted heteroarylthio group, asubstituted or unsubstituted alkylamino group, a substituted orunsubstituted dialkylamino group, a substituted or unsubstitutedcycloalkylamino group, a substituted or unsubstituted dicycloalkylaminogroup, a substituted or unsubstituted arylamino group, a substituted orunsubstituted heteroarylamino group, a substituted or unsubstitutedalkanoyl group, a substituted or unsubstituted carboxylic acid estergroup, a substituted or unsubstituted carbamoyl group, and an aminogroup optionally substituted by amino-protecting group(s); and

R4 is any of a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, a halogen atom, a substituted orunsubstituted alkoxy group, a substituted or unsubstituted aryloxygroup, a substituted or unsubstituted heteroaryloxy group, a substitutedor unsubstituted alkylthio group, a substituted or unsubstitutedarylthio group, a substituted or unsubstituted heteroarylthio group, asubstituted or unsubstituted alkylamino group, a substituted orunsubstituted dialkylamino group, a substituted or unsubstitutedcycloalkylamino group, a substituted or unsubstituted dicycloalkylaminogroup, a substituted or unsubstituted arylamino group, a substituted orunsubstituted heteroarylamino group, and an amino group optionallysubstituted by amino-protecting group(s),

or a pharmaceutically acceptable salt thereof.

(3) The azole compound of the above-mentioned (1), wherein, in formulaI,

R2 is any of a hydrogen atom, a substituted or unsubstituted lower alkylgroup, a substituted or unsubstituted aralkyl group, and a hydroxylgroup; and

R3 is a group represented by the following formula II:

wherein

R4 is any of a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstitutedcycloalkenyl group, a substituted or unsubstituted aryl group, asubstituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, a halogen atom, a substituted orunsubstituted alkoxy group, a substituted or unsubstituted aryloxygroup, a substituted or unsubstituted heteroaryloxy group, a substitutedor unsubstituted alkylthio group, a substituted or unsubstitutedarylthio group, a substituted or unsubstituted heteroarylthio group, asubstituted or unsubstituted alkylamino group, a substituted orunsubstituted dialkylamino group, a substituted or unsubstitutedarylamino group, a substituted or unsubstituted heteroarylamino group,and an amino group optionally substituted by amino-protecting group(s);and

R5 and R6 may be the same or different and each is any of a hydrogenatom and a substituted or unsubstituted lower alkyl group, or R5 and R6optionally form, together with the carbon atom bonded thereto, a 3- to8-membered ring,

or a pharmaceutically acceptable salt thereof.

(4) The azole compound of the above-mentioned (3), wherein, in formulaI,

R1 is any of a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, a halogen atom, a substituted orunsubstituted alkoxy group, a substituted or unsubstituted aryloxygroup, a substituted or unsubstituted heteroaryloxy group, a substitutedor unsubstituted alkylthio group, a substituted or unsubstitutedarylthio group, a substituted or unsubstituted heteroarylthio group, asubstituted or unsubstituted alkylamino group, a substituted orunsubstituted dialkylamino group, a substituted or unsubstitutedcycloalkylamino group, a substituted or unsubstituted dicycloalkylaminogroup, a substituted or unsubstituted arylamino group, a substituted orunsubstituted heteroarylamino group, a substituted or unsubstitutedalkanoyl group, a substituted or unsubstituted carboxylic acid estergroup, a substituted or unsubstituted carbamoyl group, and an aminogroup optionally substituted by amino-protecting group(s); and

R4 is any of a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, a halogen atom, a substituted orunsubstituted alkoxy group, a substituted or unsubstituted aryloxygroup, a substituted or unsubstituted heteroaryloxy group, a substitutedor unsubstituted alkylthio group, a substituted or unsubstitutedarylthio group, a substituted or unsubstituted heteroarylthio group, asubstituted or unsubstituted alkylamino group, a substituted orunsubstituted dialkylamino group, a substituted or unsubstitutedarylamino group, a substituted or unsubstituted heteroarylamino group,and an amino group optionally substituted by amino-protecting group(s),

or a pharmaceutically acceptable salt thereof.

(5) The azole compound of the above-mentioned (3), wherein, in formulaI, the substituent of the group for R1 is any of a cyano group and agroup represented by the following formula III:

Z-Y-X-  formula III

wherein

-   -   X and Y may be the same or different and each is any of a        substituted or unsubstituted lower alkylene group, a substituted        or unsubstituted lower alkenylene group, a substituted or        unsubstituted lower alkynylene group, a substituted or        unsubstituted cycloalkylene group, a substituted or        unsubstituted arylene group, a substituted or unsubstituted        heteroarylene group, a substituted or unsubstituted        heterocyclylene group, a carbonyl group, an oxygen atom, an        sulfur atom, a sulfinyl group, a sulfonyl group, a substituted        or unsubstituted amino group, and a bond; and    -   Z is any of a substituted or unsubstituted lower alkyl group, a        substituted or unsubstituted lower alkenyl group, a substituted        or unsubstituted lower alkynyl group, a substituted or        unsubstituted alkanoyl group, a substituted or unsubstituted        aryl group, a substituted or unsubstituted heteroaryl group, a        substituted or unsubstituted heterocyclic group, a substituted        or unsubstituted alkoxy group, a substituted or unsubstituted        aryloxy group, a substituted or unsubstituted heteroaryloxy        group, a substituted or unsubstituted alkylthio group, a        substituted or unsubstituted arylthio group, a substituted or        unsubstituted heteroarylthio group, a substituted or        unsubstituted alkylamino group, a substituted or unsubstituted        dialkylamino group, a substituted or unsubstituted        cycloalkylamino group, a substituted or unsubstituted        dicycloalkylamino group, a substituted or unsubstituted        arylamino group, a substituted or unsubstituted heteroarylamino        group, and a substituted or unsubstituted carbamoyl group,        -   wherein the substituent of the group for Z is any of a            carboxyl group, a carboxylic acid ester group, a substituted            or unsubstituted carbamoyl group, a cyano group, a hydroxyl            group, a sulfonic acid group, a sulfonamido group, a            phosphoric acid group, phosphoric acid monoester group,            phosphoric acid diester group, an amino group optionally            substituted by amino-protecting group(s), a thiol group, a            halogen atom, a substituted or unsubstituted aryl group, a            substituted or unsubstituted heteroaryl group, a substituted            or unsubstituted heterocyclic group, a substituted or            unsubstituted alkanoyl group, a substituted or unsubstituted            arylcarbonyl group, and a substituted or unsubstituted            heteroarylcarbonyl group, and the group for Z optionally has            multiple substituents described above that may be the same            or different;

R2 is any of a hydrogen atom, a substituted or unsubstituted lower alkylgroup, and a substituted or unsubstituted aralkyl group;

R4 is any of a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstitutedcycloalkenyl group, a substituted or unsubstituted aryl group, asubstituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, and a halogen atom; and

R5 and R6 may be the same or different and each is any of a hydrogenatom and a substituted or unsubstituted lower alkyl group,

or a pharmaceutically acceptable salt thereof.

(6) The azole compound of the above-mentioned (3), wherein, in formulaI, the substituent of the group for R1 is any of a hydroxyl group and agroup represented by the following formula III:

Z-Y-X-  formula III

wherein

-   -   X is any of an oxygen atom, a substituted or unsubstituted amino        group, a sulfur atom, and a bond;    -   Y is any of a carbonyl group, a sulfonyl group, and a bond; and    -   Z is any of a substituted or unsubstituted alkyl group, a        substituted or unsubstituted alkenyl group, a substituted or        unsubstituted alkynyl group, a substituted or unsubstituted        alkanoyl group, a substituted or unsubstituted aryl group, a        substituted or unsubstituted heteroaryl group, a substituted or        unsubstituted heterocyclic group, a substituted or unsubstituted        alkoxy group, a substituted or unsubstituted aryloxy group, a        substituted or unsubstituted heteroaryloxy group, a substituted        or unsubstituted alkylthio group, a substituted or unsubstituted        arylthio group, a substituted or unsubstituted heteroarylthio        group, a substituted or unsubstituted alkylamino group, a        substituted or unsubstituted dialkylamino group, a substituted        or unsubstituted cycloalkylamino group, a substituted or        unsubstituted dicycloalkylamino group, a substituted or        unsubstituted arylamino group, and a substituted or        unsubstituted heteroarylamino group,        -   wherein the substituent of the group for Z is any of a lower            alkyl group, a carboxyl group, a carboxylic acid ester            group, a substituted or unsubstituted alkanoyloxy group, a            substituted or unsubstituted carbamoyl group, a cyano group,            a hydroxyl group, a sulfonic acid group, a sulfonamido            group, a phosphoric acid group, a phosphoric acid monoester            group, a phosphoric acid diester group, an amino group            optionally substituted by amino-protecting group(s), a thiol            group, a halogen atom, a substituted or unsubstituted aryl            group, a substituted or unsubstituted heteroaryl group, a            substituted or unsubstituted heterocyclic group, a            substituted or unsubstituted alkanoyl group, a substituted            or unsubstituted arylcarbonyl group, and a substituted or            unsubstituted heteroarylcarbonyl group, and the group for Z            optionally has multiple substituents described above that            may be the same or different;

R2 is any of a hydrogen atom, a substituted or unsubstituted lower alkylgroup, and a substituted or unsubstituted aralkyl group;

R4 is any of a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstitutedcycloalkenyl group, a substituted or unsubstituted aryl group, asubstituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, and a halogen atom; and

R5 and R6 may be the same or different and each is any of a hydrogenatom and a substituted or unsubstituted lower alkyl group,

or a pharmaceutically acceptable salt thereof.

(7) The azole compound of the above-mentioned (5), wherein, in formulaI,

R1 is any of a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, a halogen atom, a substituted orunsubstituted alkoxy group, a substituted or unsubstituted aryloxygroup, a substituted or unsubstituted heteroaryloxy group, a substitutedor unsubstituted alkylthio group, a substituted or unsubstitutedarylthio group, a substituted or unsubstituted heteroarylthio group, asubstituted or unsubstituted alkylamino group, a substituted orunsubstituted dialkylamino group, a substituted or unsubstitutedcycloalkylamino group, a substituted or unsubstituted dicycloalkylaminogroup, a substituted or unsubstituted arylamino group, a substituted orunsubstituted heteroarylamino group, a substituted or unsubstitutedalkanoyl group, a substituted or unsubstituted carboxylic acid estergroup, a substituted or unsubstituted carbamoyl group, and an aminogroup optionally substituted by amino-protecting group(s); and

R4 is any of a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, and a halogen atom,

or a pharmaceutically acceptable salt thereof.

(8) The azole compound of the above-mentioned (5) or (7), wherein, informula I,

R1 is any of a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, and a substituted or unsubstitutedaralkyl group,

or a pharmaceutically acceptable salt thereof.

(9) The azole compound of the above-mentioned (2), wherein, in formulaI,

R1 is a substituted phenyl group,

-   -   wherein the substituent of the group for R1 is any of a cyano        group and a group represented by the following formula III:

Z-Y-X-  formula III

-   -    wherein        -   X is any of a methylene group and an ethylene group,        -   Y is any of a sulfur atom, a sulfinyl group, a sulfonyl            group, an oxygen atom, a substituted or unsubstituted amino            group, and a methylene group, and        -   Z is any of a substituted or unsubstituted lower alkyl            group, a substituted or unsubstituted lower alkenyl group, a            substituted or unsubstituted alkanoyl group, a substituted            or unsubstituted triazole group, and a substituted or            unsubstituted tetrazole group,            -   wherein the substituent of the group for Z is any of a                carboxyl group, an alkoxycarbonyl group, a furyl group,                a phenyl group, a hydroxyl group, a carbamoyl group, a                carbamoyl group substituted by lower alkyl group(s), a                carbamoyl group substituted by carboxy lower alkyl                group(s), a carbamoyl group substituted by lower alkyl                group(s) substituted by a furyl group, an amino group                optionally substituted by amino-protecting group(s), a                sulfonic acid group, a pyrrolylcarbonyl group, a pyridyl                group, and a halogen atom, and the group for Z                optionally has multiple substituents described above                that may be the same or different;

R2 is a hydrogen atom; and

R3 is a group represented by the following formula II:

wherein

R4 is a substituted or unsubstituted phenyl group wherein thesubstituent of the group for R4 is a halogen atom,

R5 is any of a hydrogen atom, a lower alkyl group, and a lower alkylgroup substituted by 1 to 3 halogen atoms, and

R6 is a hydrogen atom,

or a pharmaceutically acceptable salt thereof.

(10) The azole compound of the above-mentioned (6), wherein, in formulaI,

R1 is any of a substituted or unsubstituted phenyl group, a substitutedor unsubstituted heteroaryl group, a substituted or unsubstitutedheterocyclic group, a substituted or unsubstituted cycloalkyl group, anda substituted or unsubstituted cycloalkenyl group

-   -   wherein the substituent of the group for R1 is any of a hydroxyl        group and a group represented by the following formula III:

Z-Y-X-  formula III

-   -    wherein        -   X is any of an oxygen atom, a substituted or unsubstituted            amino group, a sulfur atom, and a bond,        -   Y is any of a carbonyl group, a sulfonyl group, and a bond,            and        -   Z is a substituted or unsubstituted alkyl group,            -   wherein the substituent of the group for Z is any of a                lower alkyl group, a carboxyl group, a carboxylic acid                ester group, a substituted or unsubstituted alkanoyloxy                group, a substituted or unsubstituted carbamoyl group, a                cyano group, a hydroxyl group, a sulfonic acid group, a                sulfonamido group, a phosphoric acid group, a phosphoric                acid monoester group, a phosphoric acid diester group,                an amino group optionally substituted by                amino-protecting group(s), a thiol group, a halogen                atom, a substituted or unsubstituted aryl group, a                substituted or unsubstituted heteroaryl group, a                substituted or unsubstituted heterocyclic group, a                substituted or unsubstituted alkanoyl group, a                substituted or unsubstituted arylcarbonyl group, and a                substituted or unsubstituted heteroarylcarbonyl group,                and the group for Z optionally has multiple substituents                described above that may be the same or different,                or a pharmaceutically acceptable salt thereof.

(11) The azole compound of the above-mentioned (5), wherein, in formulaI,

R1 is any of a substituted or unsubstituted aryl group, a substituted orunsubstituted heteroaryl group, a substituted or unsubstitutedheterocyclic group, a substituted or unsubstituted cycloalkyl group, anda substituted or unsubstituted cycloalkenyl group,

-   -   wherein the substituent of the group for R1 is a group        represented by the following formula III:

Z-Y-X-  formula III

-   -   wherein each symbol is as defined in the above-mentioned (5),

R2 is a hydrogen atom;

R4 is any of a substituted or unsubstituted aryl group, a substituted orunsubstituted heteroaryl group, a substituted or unsubstitutedheterocyclic group, a substituted or unsubstituted cycloalkyl group, anda substituted or unsubstituted cycloalkenyl group;

R5 is a substituted or unsubstituted lower alkyl group; and

R6 is a hydrogen atom,

or a pharmaceutically acceptable salt thereof.

(12) The azole compound of the above-mentioned (11), wherein, in formulaI,

R4 is a substituted or unsubstituted cycloalkenyl group,

or a pharmaceutically acceptable salt thereof.

(13) The azole compound of any of the above-mentioned (1) to (12),wherein, in formula I,

ring A is ring-1,

or a pharmaceutically acceptable salt thereof.

(14) The azole compound of any of the above-mentioned (1) to (12),wherein, in formula I,

ring A is ring-2,

or a pharmaceutically acceptable salt thereof.

(15) The azole compound of any of the above-mentioned (1) to (12),wherein, in formula I,

ring A is ring-3,

or a pharmaceutically acceptable salt thereof.

(16) The azole compound of any of the above-mentioned (1) to (12),wherein, in formula I,

ring A is ring-4,

or a pharmaceutically acceptable salt thereof.

(17) The azole compound of any of the above-mentioned (1) to (12),wherein, in formula I,

ring A is ring-5,

or a pharmaceutically acceptable salt thereof.

(18) The azole compound of any of the above-mentioned (1) to (12),wherein, in formula I,

ring A is ring-6,

or a pharmaceutically acceptable salt thereof.

(19) The azole compound of any of the above-mentioned (1) to (12),wherein, in formula I,

ring A is ring-7,

or a pharmaceutically acceptable salt thereof.

(20) The azole compound of any of the above-mentioned (1) to (12),wherein, in formula I,

ring A is ring-8,

or a pharmaceutically acceptable salt thereof.

(21) The azole compound of any of the above-mentioned (1) to (12),wherein, in formula I,

ring A is ring-9,

or a pharmaceutically acceptable salt thereof.

(22) The azole compound of any of the above-mentioned (1) to (12),wherein, in formula I,

ring A is ring-10,

or a pharmaceutically acceptable salt thereof.

(23) The azole compound of the above-mentioned (10), wherein, in formulaI, ring A is any of ring-1 and ring-2; and

R1 is a substituted phenyl group,

-   -   wherein the substituent of the group for R1 is any of a hydroxyl        group and a group represented by the following formula M:

Z-Y-X-  formula III

-   -    wherein        -   X is any of an oxygen atom and a substituted or            unsubstituted amino group,        -   Y is any of a carbonyl group and a bond, and        -   Z is a substituted or unsubstituted alkyl group            -   wherein the substituent of the group for Z is any of a                lower alkyl group, a carboxyl group, a carboxylic acid                ester group, a substituted or unsubstituted alkanoyloxy                group, a substituted or unsubstituted carbamoyl group, a                cyano group, a hydroxyl group, a sulfonic acid group, a                sulfonamido group, a phosphoric acid group, a phosphoric                acid monoester group, a phosphoric acid diester group,                an amino group optionally substituted by                amino-protecting group(s), a thiol group, a halogen                atom, a substituted or unsubstituted aryl group, a                substituted or unsubstituted heteroaryl group, a                substituted or unsubstituted heterocyclic group, a                substituted or unsubstituted alkanoyl group, a                substituted or unsubstituted arylcarbonyl group, and a                substituted or unsubstituted heteroarylcarbonyl group,                and the group for Z optionally has multiple substituents                described above that may be the same or different,                or a pharmaceutically acceptable salt thereof.

(24) The azole compound of the above-mentioned (11), wherein, in formulaI, ring A is any of ring-1 and ring-2;

R1 is a substituted phenyl group;

X is any of a substituted or unsubstituted methylene group, asubstituted or unsubstituted ethylene group and a substituted orunsubstituted vinylene group;

Y is any of a sulfur atom, a sulfonyl group, a substituted orunsubstituted methylene group, and an oxygen atom;

Z is any of a substituted methyl group, a substituted ethyl group, asubstituted propyl group, and a substituted carbamoyl group,

-   -   wherein the substituent of the group for Z is any of a carboxyl        group, a carboxylic acid ester group, an acetylamino group, a        sulfonic acid group, and a hydroxyl group, and the group for Z        optionally has multiple substituents described above that may be        the same or different;

R4 is any of a substituted phenyl group, a substituted cyclopentenylgroup, a substituted cyclohexenyl group, and a substituted thienylgroup,

-   -   wherein the substituent of the group for R4 is any of a chlorine        atom, a bromine atom and a substituted or unsubstituted lower        alkyl group; and

R5 is a methyl group,

or a pharmaceutically acceptable salt thereof.

(25) The azole compound of the above-mentioned (23), wherein, in formulaI,

the substituent of the group for R1 is any of a hydroxyl group and agroup represented by the following formula III:

Z-Y-X-  formula III

-   -   wherein    -   X is any of an oxygen atom and a substituted or unsubstituted        amino group,    -   Y is any of a carbonyl group and a bond, and    -   Z is a substituted or unsubstituted alkyl group,        -   wherein the substituent of the group for Z is any of a lower            alkyl group, a carboxyl group, a carboxylic acid ester            group, an alkanoyloxy group, a hydroxyl group, a sulfonic            acid group, and an amino group optionally substituted by            amino-protecting group(s), and the group for Z optionally            has multiple substituents described above that may be the            same or different,            or a pharmaceutically acceptable salt thereof.

(26) The azole compound of the above-mentioned (24), wherein, in formulaI,

X is any of a methylene group, a ethylene group, and a vinylene group;

Y is any of a sulfur atom, a sulfonyl group), a methylene group, and anoxygen atom;

Z is any of a substituted methyl group, a substituted ethyl group, asubstituted propyl group, and a substituted carbamoyl group,

-   -   wherein the substituent of the group for Z is any of a carboxyl        group, a carboxylic acid ester group, an acetylamino group, and        a sulfonic acid group, and the group for Z optionally has        multiple substituents described above that may be the same or        different; and

R4 is any of a substituted phenyl group, a substituted cyclopentenylgroup, and a substituted cyclohexenyl group,

-   -   wherein the substituent of the group for R4 is any of a chlorine        atom and a bromine atom,        or a pharmaceutically acceptable salt thereof.

(27) A pharmaceutical agent comprising the compound of any of theabove-mentioned (1) to (26) as an active ingredient.

(28) The pharmaceutical agent of the above-mentioned (27), which is aninhibitor of the physiological activity of LPA.

(29) The pharmaceutical agent of the above-mentioned (27), which is anagent for the prophylaxis or treatment of liver disease.

(30) The pharmaceutical agent of the above-mentioned (27), which is anagent for the prophylaxis or treatment of organ fibrosis.

(31) The pharmaceutical agent of the above-mentioned (27), which is anagent for improving liver function.

(32) A pharmaceutical composition comprising the compound of any of theabove-mentioned (1) to (26) as an active ingredient and apharmaceutically acceptable carrier.

(33) A method of inhibiting the physiological activity of LPA, whichcomprises administering an effective amount of the compound of any ofthe above-mentioned (1) to (26) to a mammal.

(34) A method for the prophylaxis or treatment of hepatic disease, whichcomprises administering an effective amount of the compound of any ofthe above-mentioned (1) to (26) to a mammal.

(35) A method for the prophylaxis or treatment of organ fibrosis, whichcomprises administering an effective amount of the compound of any ofthe above-mentioned (1) to (26) to a mammal.

(36) A method of improving liver function, which comprises administeringan effective amount of the compound of any of the above-mentioned (1) to(26) to a mammal.

(37) Use of the compound of any of the above-mentioned (1) to (26) forthe production of an inhibitor of the physiological activity of LPA.

(38) Use of the compound of any of the above-mentioned (1) to (26) forthe production of an agent for the prophylaxis or treatment of hepaticdisease.

(39) Use of the compound of any of the above-mentioned (1) to (26) forthe production of an agent for the prophylaxis or treatment of organfibrosis.

(40) Use of the compound of any of the above-mentioned (1) to (26) forthe production of an agent for improving liver function.

(41) A commercial package comprising the pharmaceutical composition ofthe above-mentioned (32), and a written matter associated therewith, thewritten matter stating that the pharmaceutical composition can or shouldbe used for inhibiting the physiological activity of LPA.

(42) A commercial package comprising the pharmaceutical composition ofthe above-mentioned (32), and a written matter associated therewith, thewritten matter stating that the pharmaceutical composition can or shouldbe used for the prophylaxis or treatment of liver disease.

(43) A commercial package comprising the pharmaceutical composition ofthe above-mentioned (32), and a written matter associated therewith, thewritten matter stating that the pharmaceutical composition can or shouldbe used for the prophylaxis or treatment of organ fibrosis.

(44) A commercial package comprising the pharmaceutical composition ofthe above-mentioned (32), and a written matter associated therewith, thewritten matter stating that the pharmaceutical composition can or shouldbe used for improving liver function.

EFFECT OF THE INVENTION

The present invention provides compounds which inhibit the physiologicalactivity of LPA and pharmaceutically acceptable salts thereof. Suchcompounds are useful for the prophylaxis or treatment of fibrosis oforgans (liver, kidney, lung, and the like), hepatic disease (acute orchronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension,regenerative failure, non-alcoholic steatohepatitis (NASH), liverhypofunction, hepatic blood flow disorder, and the like), cellproliferative disease (cancer (solid tumor, solid tumor metastasis,vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia,and the like) and invasive metastasis of cancer cell and the like),inflammatory disease (psoriasis, nephropathy, pneumonia, and the like),gastrointestinal tract disease (irritable bowel syndrome (IBS),inflammatory bowel disease (IBD), abnormal pancreatic secretion, and thelike), renal disease, urinary tract-associated disease (benign prostatichyperplasia or symptoms associated with neuropathic bladder disease,spinal cord tumor, hernia of intervertebral disk, spinal canal stenosis,symptoms derived from diabetes, lower urinary tract disease (obstructionof lower urinary tract and the like), inflammatory disease of lowerurinary tract, dysuria, frequent urination, and the like), pancreasdisease, abnormal angiogenesis-associated disease (arterial obstructionand the like), brain-associated disease (cerebral infarction, cerebralhemorrhage, and the like), peripheral neuropathy, and the like. Suchcompounds and pharmaceutical compositions are particularly useful forthe prophylaxis or treatment of fibrosis of organs (liver, kidney, lung,and the like) and liver diseases.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The action to “inhibit the physiological activity of LPA” in the presentinvention may be any as long as the physiological activity of LPA isfinally inhibited (LPA inhibitory action). For example, it may be anaction to suppress production of LPA itself, or an action to antagonizeLPA receptors. Preferably, the compounds of the present inventioninhibit the physiological activity of LFA by an LPA receptorantagonistic action.

In the present invention, the “improvement of liver function” meansimproving test value that worsens when suffering a hepatic disease. Forexample, improvement of an increase in γ-GTP, improvement of a decreasedin total protein and albumin value, improvement of a prolongedprothrombin time, improvement of a decrease in the total cholesterolvalue, improvement of an increase in bile acid value, improvement of anincrease in hyaluronic acid value, improvement of a decrease in plateletcount, and the like can be mentioned.

As the “alkyl group” in the present invention, for example, a straightor branched chain C₁₋₁₀ alkyl group such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,3,3-dimethylpropyl, 2-ethylbutyl, n-heptyl, 1-methylheptyl,1-ethylhexyl, n-octyl, 1-methylheptyl, nonyl, and the like, and the likecan be mentioned.

In addition, as the “lower alkyl group” in the present invention, forexample, a straight C₁₋₆ alkyl group such as methyl, ethyl, n-propyl,n-butyl, n-pentyl, n-hexyl, and the like, a branched chain C₁₋₆ alkylgroup such as isopropyl, isobutyl, neopentyl, sec-butyl, tert-butyl, andthe like, and the like can be mentioned.

As the “cycloalkyl group” in the present invention, for example, a C₃₋₉cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and the like, and thelike can be mentioned.

The cycloalkyl moiety of the “cycloalkylene group” in the presentinvention is as defined for the above-mentioned cycloalkyl group.

As the “cycloalkenyl group” in the present invention, for example, aC₃₋₉ cycloalkenyl group such as cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl,and the like, and the like can be mentioned.

As the “alkenyl group” in the present invention, for example, a straightor branched chain C₂₋₈ alkenyl group such as vinyl, allyl, isopropenyl,2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl,3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl,1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl,1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl,1-octenyl, and the like, and the like can be mentioned.

In addition, as the “lower alkenyl group” in the present invention, astraight or branched chain C₂₋₆ alkenyl group and the like can bementioned.

As the “alkynyl group” in the present invention, for example, a straightor branched chain C₂₋₈ alkynyl group such as ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,5-hexynyl, 1-heptynyl, 1-octynyl, and the like can be mentioned.

In addition, as the “lower alkynyl group” in the present invention, astraight or branched chain C₂₋₆ alkynyl group and the like can bementioned.

The alkyl moiety of the “alkoxy group” in the present invention is asdefined for the above-mentioned alkyl group, and similarly, the alkylmoiety of the “lower alkoxy group” is as defined for the above-mentionedlower alkyl group.

The “aryl group” in the present invention is preferably a monocyclic totricyclic aromatic hydrocarbon group having 6 to 14 carbon atoms. Morepreferably, phenyl, naphthyl, indenyl, and the like can be mentioned.

Moreover, the phenyl group may be condensed with a 5- to 8-memberedcycloalkyl ring to form indanyl or tetrahydronaphthyl group.

The aryl moiety of the “arylene group” in the present invention is asdefined for the above-mentioned aryl group.

The aryl moiety of the “aryloxy group” in the present invention is asdefined for the above-mentioned aryl group.

The aryl moiety of the “arylcarbonyl group” in the present invention isas defined for the above-mentioned aryl group.

The “aralkyl group” in the present invention means an arylalkyl group,wherein the aryl moiety and the alkyl moiety are as defined for theabove-mentioned aryl group and the above-mentioned alkyl group,respectively. For example, a C₇₋₁₀ aralkyl group such as benzyl,phenethyl and the like, and the like can be mentioned.

As the “heteroaryl group” in the present invention, a 5- to 8-membered,monocyclic to tricyclic aromatic heterocyclic group containing, as ringatom(s) besides carbon atom(s), 1 to 4 heteroatoms selected from anoxygen atom, a sulfur atom, and a nitrogen atom can be mentioned,wherein a sulfur atom or a nitrogen atom may be oxidized to form anoxide. Preferably, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, furyl,thienyl, pyrrolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl,pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl,[κ1]tetrazolyl, benzofuranyl, benzothienyl, indolyl, isoindolyl,benzoxazolyl, benzothiazolyl, benzimidazolyl, indazolyl, benzisoxazolyl,benzisothiazolyl, benzofurazanyl, benzothiadiazolyl, purinyl, quinolyl,isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,pteridinyl, imidazoxazolyl, imidazothiazolyl, imidazoimidazolyl,dibenzofuranyl, dibenzothienyl, carbazolyl, acridinyl, and the like canbe mentioned.

The heteroaryl moiety of the “heteroarylene group” in the presentinvention is as defined for the above-mentioned heteroaryl group.

The heteroaryl moiety of the “heteroaryloxy group” in the presentinvention is as defined for the above-mentioned heteroaryl group.

The heteroaryl moiety of the “heteroarylcarbonyl group” in the presentinvention is as defined for the above-mentioned heteroaryl group.

As the “heterocyclic group” in the present invention, a 5- to8-membered, monocyclic to tricyclic heterocyclic group containing, asring atom(s) besides carbon atom(s), 1 to 4 heteroatoms selected from anoxygen atom, a sulfur atom, and a nitrogen atom can be mentioned,wherein any carbon atom, which is a ring atom, may be substituted by anoxo group, and a sulfur atom or a nitrogen atom may be oxidized to formoxide. In addition, the heterocyclic group may be condensed with abenzene ring, may be crosslinked, and may form a spiro ring. Preferably,pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, furyl, thienyl, pyrrolyl,isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyrazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, thiazolyl, tetrazolyl, benzofuranyl,benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl,benzimidazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl,benzofurazanyl, benzothiadiazolyl, purinyl, quinolyl, isoquinolyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, pteridinyl,imidazoxazolyl, imidazothiazolyl, imidazimidazolyl, dibenzofuranyl,dibenzothienyl, carbazolyl, acridinyl, pyrrolidinyl, pyrazolidinyl,imidazolidinyl, pyrrolinyl, pyrazolinyl, imidazolinyl,tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, piperidinyl,piperazinyl, quinuclidinyl, tetrahydropyranyl, morpholinyl, dioxolanyl,homopiperidinyl, homopiperazinyl, indolinyl, isoindolinyl, chromanyl,isochromanyl, 8-azabicyclo[3.2.1]octan-3-yl,9-azabicyclo[3.3.1]nonan-3-yl, 3-azabicyclo[3.2.1]octan-6-yl,7-azabicyclo[2.2.1]heptan-2-yl, 2-azatricyclo[3.3.1.1]decan-4-yl,1-azabicyclo[2.2.2]octan-2-yl, 1-azabicyclo[2.2.2]octan-3-yl,1-azabicyclo[2.2.2]octan-4-yl, 3-azaspiro[5.5]undecan-9-yl,2-azaspiro[4.5]decan-8-yl, 2-azaspiro[4.4]nonan-7-yl,8-azaspiro[4.5]decan-2-yl, and the like can be mentioned.

The heterocyclic moiety of the “heterocyclylene group” in the presentinvention is as defined for the above-mentioned heterocyclic group.

The alkyl moiety of the “alkylthio group” in the present invention is asdefined for the above-mentioned alkyl group.

The aryl moiety of the “arylthio group” in the present invention is asdefined for the above-mentioned aryl group.

The heteroaryl moiety of the “heteroarylthio group” in the presentinvention is as defined for the above-mentioned heteroaryl group.

The “alkanoyl group” in the present invention refers to an aliphaticacyl group and, for example, a C₁₋₆ alkanoyl group such as formyl,acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl,hexanoyl, and the like, and the like can be mentioned.

The alkanoyl moiety of the “alkanoyloxy group” in the present inventionis as defined for the above-mentioned alkanoyl group.

As the “alkylamino group” in the present invention, an alkylamino groupwherein one hydrogen atom of the amino group is substituted by theabove-mentioned alkyl group can be mentioned. As the “dialkylaminogroup” in the present invention, a dialkylamino group wherein twohydrogen atoms of the amino group are substituted by the above-mentionedalkyl groups can be mentioned.

As the “cycloalkylamino group” in the present invention, acycloalkylamino group wherein one hydrogen atom of the amino group issubstituted by the above-mentioned cycloalkyl group can be mentioned. Asthe “dicycloalkylamino group” in the present invention, adicycloalkylamino group wherein two hydrogen atoms of the amino groupare substituted by the above-mentioned cycloalkyl groups can bementioned.

As the “arylamino group” in the present invention, an arylamino groupwherein one hydrogen atom of the amino group is substituted by theabove-mentioned aryl group can be mentioned.

As the “heteroarylamino group” in the present invention, aheteroarylamino group wherein one hydrogen atom of the amino group issubstituted by the above-mentioned heteroaryl group can be mentioned.

As the “carboxylic acid ester group” in the present invention, forexample, an alkoxycarbonyl group, an aryloxycarbonyl group, anaralkyloxycarbonyl group, and the like can be mentioned. The alkoxymoiety, aryl moiety and aralkyl moiety of these are as defined for theabove-mentioned “alkoxy group.” “aryl group,” and “aralkyl group,”respectively. For example, methoxycarbonyl, elhoxycarbonyl,phenoxycarbonyl, benzyloxycarbonyl, and the like can be mentioned.

As the “phosphoric acid diester group” in the present invention, forexample, a dialkoxyphosphono group, a diaryloxyphosphono group, adiaralkyloxyphosphono group, and the like can be mentioned.

As the “phosphoric acid monoester group” in the present invention, forexample, an alkoxy-hydroxy-phosphono group, an aryloxy-hydroxy-phosphonogroup, an aralkyloxy-hydroxy-phosphono group, and the Like can bementioned.

The alkoxy moiety, the aryl moiety and the aralkyl moiety of these areas defined for the above-mentioned “alkoxy group,” “aryl group,” and“aralkyl group,” respectively.

The “halogen atom” in the present invention refers to each atom offluorine, chlorine, bromine, and iodine.

As the “lower alkylene group” in the present invention, for example, astraight or branched chain C₁₋₆ alkylene group such as methylene,ethylene, propylene, butylene, pentamethylene, hexamethylene, and thelike, and the like can be mentioned.

As the “lower alkenylene group” in the present invention, for example, astraight or branched chain C₂₋₆ alkenylene group such as vinylene,propenylene, [κ2]1-butenylene, 2-butenylene, 1-pentenylene,2-pentenylene, 3-pentenylene, 1-hexenylene, and the like, and the likecan be mentioned.

As the “lower alkynylene group” in the present invention, for example, astraight or branched chain C₂₋₆ alkynylene group such as ethynylene,propynylene, 1-butynylene, 2-butynylene, 1-pentynylene, 2-pentynylene,3-pentynylene, 1-hexynylene, and the like, and the like can bementioned.

As the “3- to 8-membered ring formed by R5 and R6 together with thecarbon atom bonded thereto” in the present invention, for example, asaturated or unsaturated hydrocarbon ring such as a cycloalkane (e.g.,cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane,cyclooctane, etc.), a cycloalkene (e.g., cyclopropene, cyclobutene,cyclopentene, cyclohexene, cycloheptene, cyclooctene, etc.), and thelike, and a saturated or unsaturated heterocycle further containing,besides carbon atom(s), a nitrogen atom, an oxygen atom or a sulfuratom, such as pyrrolidine, tetrahydrofuran, tetrahydrothiophene,piperidine, morpholine, thiomorpholine, piperazine, and the like can bementioned.

The “amino-protecting group” of “amino group optionally substituted byamino-protecting group(s)” in the present invention refers to aprotecting group generally used for protecting an amino group fromvarious reactions. For example, an acyl group such as a formyl group, anacetyl group, a trifluoroacetyl group, a pivaloyl group, and the like;an alkoxycarbonyl group such as a methoxycarbonyl group, aethoxycarbonyl group, a tert-butoxycarbonyl group, a(fluoren-9-yl)methoxycarbonyl group, and the like; and the like can bementioned.

As the substituent of the substituted alkyl group (including lower alkylgroup), substituted alkoxy group and substituted alkanoyl group in thepresent invention, for example, a lower alkyl group, a lower alkoxygroup, a lower alkoxycarbonyl group, a hydroxy group, a halogen atom, anamino group, a thio group, a lower alkylamino group, a lower alkylthiogroup, a carboxyl group, a nitro group, a cyano group, an amido group,an aryl group, a substituted aryl group, a heterocyclic group, asubstituted heterocyclic group, a group represented by the followingformula III:

Z-Y-X-  formula III

-   -   wherein X and Y may be the same or different and each is any of        a substituted or unsubstituted lower alkylene group, a        substituted or unsubstituted lower alkenylene group, a        substituted or unsubstituted lower alkynylene group, a        substituted or unsubstituted cycloalkylene group, a substituted        or unsubstituted arylene group, a substituted or unsubstituted        heteroarylene group, a substituted or unsubstituted        heterocyclylene group, a carbonyl group, an oxygen atom, a        sulfur atom, a sulfinyl group, a sulfonyl group, a substituted        or unsubstituted amino group, and a bond, and    -   Z is any of a substituted or unsubstituted alkyl group, a        substituted or unsubstituted alkenyl group, a substituted or        unsubstituted alkynyl group, a substituted or unsubstituted        alkanoyl group, a substituted or unsubstituted aryl group, a        substituted or unsubstituted heteroaryl group, a substituted or        unsubstituted heterocyclic group, a substituted or unsubstituted        alkoxy group, a substituted or unsubstituted aryloxy group, a        substituted or unsubstituted heteroaryloxy group, a substituted        or unsubstituted alkylthio group, a substituted or unsubstituted        arylthio group, a substituted or unsubstituted heteroarylthio        group, a substituted or unsubstituted alkylamino group, a        substituted or unsubstituted dialkylamino group, a substituted        or unsubstituted cycloalkylamino group, a substituted or        unsubstituted dicycloalkylamino group, a substituted or        unsubstituted arylamino group, a substituted or unsubstituted        heteroarylamino group, and a substituted or unsubstituted        carbamoyl group,        -   wherein the substituent of the group for Z is any of a lower            alkyl group, a carboxyl group, a carboxylic acid ester            group, a substituted or unsubstituted alkanoyloxy group, a            substituted or unsubstituted carbamoyl group, a cyano group,            a hydroxyl group, a sulfonic acid group, a sulfonamido            group, a phosphoric acid group, a phosphoric acid monoester            group, a phosphoric acid diester group, an amino group            optionally substituted by amino-protecting group(s), a thiol            group, a halogen atom, a substituted or unsubstituted aryl            group, a substituted or unsubstituted heteroaryl group, a            substituted or unsubstituted heterocyclic group, a            substituted or unsubstituted alkanoyl group, a substituted            or unsubstituted arylcarbonyl group, and a substituted or            unsubstituted heteroarylcarbonyl group, and the group for Z            optionally has the same or different multiple substituents            selected from the substituents,            and the like can be mentioned.

The lower alkyl, lower alkoxy, aryl and heterocyclic group here are asdefined above, respectively. In addition, each group for each symbol informula III is also as defined above.

The number of the substituents of the substituted alkyl group,substituted alkoxy group and substituted alkanoyl group is preferably 1to 3, and when multiple substituents are used, they may be the same ordifferent.

As the substituent of the substituted alkenyl group or substitutedalkynyl group in the present invention, a substituted or unsubstitutedlower alkyl group, a substituted or unsubstituted aryl group, asubstituted or unsubstituted heteroaryl group, a carboxyl group, acarboxylic acid ester group, an amido group, a nitro group, a cyanogroup, a halogen atom, a hydroxyl group, a group represented by thefollowing formula III:

Z-Y-X-  formula III

-   -   wherein each symbol is as defined above, and the like can be        mentioned.

The lower alkyl group, aryl group, heteroaryl group, carboxylic acidester group, and halogen atom here are as defined above.

The number of the substituents of the substituted alkenyl group and thesubstituted alkynyl group is preferably 1 to 3, and when multiplesubstituents are used, they may be the same or different.

As the substituent of the substituted cycloalkyl group, the substitutedcycloalkenyl group, the substituted aryl group, the substitutedheteroaryl group, and the substituted heterocyclic group in the presentinvention, for example, a substituted or unsubstituted lower alkylgroup, a substituted or unsubstituted lower alkenyl group, a substitutedor unsubstituted lower alkynyl group, a substituted or unsubstitutedlower alkoxy group, a substituted or unsubstituted lower alkylthiogroup, a substituted or unsubstituted lower alkylsulfinyl group, asubstituted or unsubstituted lower alkylsulfonyl group, a substituted orunsubstituted lower alkylamino group, a substituted or unsubstitutedlower alkanoyl group, a halogen atom, a carboxyl group, a substituted orunsubstituted lower alkoxycarbonyl group, a hydroxyl group, a nitrogroup, a substituted or unsubstituted amino group, a cyano group, asubstituted or unsubstituted amido group, a group represented by thefollowing formula III:

Z-Y-X-  formula III

-   -   wherein each symbol is as defined above,        and the like can be mentioned.

The number of the substituents of the substituted cycloalkyl group, thesubstituted cycloalkenyl group, the substituted aryl group, thesubstituted heteroaryl group, and the substituted heterocyclic group ispreferably 1 to 6, and when multiple substituents are used, they may bethe same or different.

As the substituent of the substituted lower alkylene group, thesubstituted lower alkenylene group, and the substituted lower alkynylenegroup in the present invention, a substituted or unsubstituted loweralkyl group, a substituted or unsubstituted aryl group, a substituted orunsubstituted heteroaryl group, a carboxyl group, a carboxylic acidester group, an amido group, a nitro group, a cyano group, a halogenatom, a hydroxyl group, and the like can be mentioned. The lower alkylgroup, aryl group, heteroaryl group, carboxylic acid ester group, andhalogen atom here are as defined above.

The number of the substituents of the substituted lower alkylene group,the substituted lower alkenylene group, and the substituted loweralkynylene group is preferably 1 to 3, and when multiple substituentsare used, they may be the same or different.

The substituents and the number thereof of the substituted alkyl moiety(including lower alkyl moiety) of the substituted alkylthio group(including lower alkylthio group), the substituted alkylamino group, thesubstituted dialkylamino group, and the substituted aralkyl group in thepresent invention are as defined with regard to the above-mentionedsubstituted alkyl group. In addition, the substituents and the numberthereof of the substituted cycloalkyl moiety, substituted aryl moiety,and substituted heteroaryl moiety of the substituted cycloalkylaminogroup, the substituted dicycloalkylamino group, the substituted aralkylgroup, the substituted arylamino group, the substituted aryloxy group,the substituted arylthio group, the substituted heteroaryloxy group, thesubstituted heteroarylthio group, and the substituted heteroarylaminogroup are as defined with regard to the above-mentioned substitutedcycloalkyl group.

As the substituted carboxylic acid ester group in the present invention,a substituted alkoxycarbonyl group, a substituted aryloxycarbonyl group,a substituted aralkyloxycarbonyl group, and the like can be mentioned.The substituents and the number thereof of the substituted alkoxy moietyof the substituted alkoxycarbonyl group are as defined with regard tothe above-mentioned substituted alkoxy group. The substituents and thenumber thereof of the substituted aryl moiety of the substitutedaryloxycarbonyl group and the substituted aralkyloxycarbonyl group areas defined with regard to the above-mentioned substituted aryl group.The substituents and the number thereof of the substituted alkyl moietyof the substituted aralkyloxycarbonyl group are as defined with regardto the above-mentioned substituted alkyl group.

The substituent of the substituted methylene group in the presentinvention is as defined with regard to the above-mentioned substitutedalkylene group. The number of substituents of these groups is 1 or 2.

As the substituent of the substituted carbamoyl group in the presentinvention, for example, a substituted or unsubstituted alkyl group, asubstituted or unsubstituted aryl group, a substituted or unsubstitutedheteroaryl group, a substituted or unsubstituted aralkyl group, or analkyl group substituted by a substituted or unsubstituted heteroarylgroup, and the like can be mentioned. Here, the alkyl group, aryl group,heteroaryl group, aralkyl group, and substituent thereof are as definedabove.

As ring A in formula I, ring-1, ring-2, and ring-6 are preferable. Ofthese, ring-1 and ring-2 are particularly preferable.

As R1 in formula I, a substituted or unsubstituted alkyl group, asubstituted or unsubstituted cycloalkyl group, a substituted orunsubstituted cycloalkenyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, and a substituted or unsubstitutedaralkyl group are preferable. Of these, a substituted or unsubstitutedaryl group (particularly a substituted or unsubstituted phenyl group)and a substituted or unsubstituted heteroaryl group are particularlypreferable.

As the substituent of the group for R1 in formula I, a cyano group, ahydroxyl group and a group represented by the following formula III:

Z-Y-X-  formula III

wherein each symbol is as defined above,

are preferable.

As X in formula III, a substituted or unsubstituted lower alkylenegroup, a substituted or unsubstituted lower alkenylene group, an oxygenatom, a substituted or unsubstituted amino group, a sulfur atom, and abond are preferable. Of these, a substituted or unsubstituted methylenegroup, a substituted or unsubstituted ethylene group, a substituted orunsubstituted vinylene group, an oxygen atom, and a substituted orunsubstituted amino group are preferable, and a unsubstituted methylenegroup, a unsubstituted ethylene group, a unsubstituted vinylene group,an oxygen atom, and a unsubstituted amino group are particularlypreferable.

As Y in formula III, a sulfur atom, a sulfinyl group, a sulfonyl group,an oxygen atom, a substituted or unsubstituted amino group, asubstituted or unsubstituted lower alkylene group, a carbonyl group, anda bond are preferable. Of these, a sulfur atom, a sulfonyl group, anoxygen atom, a substituted or unsubstituted methylene group, a carbonylgroup, and a bond are preferable; a sulfur atom, a sulfonyl group, aunsubstituted methylene group, a carbonyl group, and a bond areparticularly preferable.

Those of ordinary skill in the art can understand possible combinationsof X and Y in formula III and can make appropriate selection.

As Z in formula III, a substituted or unsubstituted alkyl group, asubstituted or unsubstituted alkanoyl group, a substituted orunsubstituted aryl group, a substituted or unsubstituted heteroarylgroup, and a substituted or unsubstituted heterocyclic group arepreferable. Of these, a substituted methyl group, a substituted ethylgroup, and a substituted propyl group are preferable.

As the substituent of the group for Z, a lower alkyl group, a carboxylgroup, a carboxylic acid ester group, an alkanoyloxy group, an aminogroup optionally substituted by amino-protecting group(s) (includingacetylamino group), a sulfonic acid group, and a hydroxyl group arepreferable, and the number of the substituents is preferably 1 or 2.

As R2 in formula I, a hydrogen atom, a substituted or unsubstitutedlower alkyl group, and a substituted or unsubstituted aralkyl group arepreferable. Of these, a hydrogen atom is particularly preferable.

As R3 in formula I, a group represented by the following formula II:

wherein

-   -   R4 is any of a substituted or unsubstituted alkyl group, a        substituted or unsubstituted cycloalkyl group, a substituted or        unsubstituted cycloalkenyl group, a substituted or unsubstituted        aryl group, a substituted or unsubstituted heteroaryl group, a        substituted or unsubstituted heterocyclic group, a substituted        or unsubstituted aralkyl group, a substituted or unsubstituted        alkenyl group, a substituted or unsubstituted alkynyl group, a        halogen atom, a substituted or unsubstituted alkoxy group, a        substituted or unsubstituted aryloxy group, a substituted or        unsubstituted heteroaryloxy group, a substituted or        unsubstituted alkylthio group, a substituted or unsubstituted        arylthio group, a substituted or unsubstituted heteroarylthio        group, a substituted or unsubstituted alkylamino group, a        substituted or unsubstituted dialkylamino group, a substituted        or unsubstituted arylamino group, a substituted or unsubstituted        heteroarylamino group, and an amino group optionally substituted        by amino-protecting group(s), and    -   R5 and R6 may be the same or different and each is any of a        hydrogen atom and a substituted or unsubstituted lower alkyl        group, or R5 and R6 optionally form, together with the carbon        atom bonded thereto, a 3- to 8-membered ring,        is preferable.

As R4 in formula II, a substituted or unsubstituted alkyl group, asubstituted or unsubstituted cycloalkyl group, a substituted orunsubstituted cycloalkenyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, and a halogen atom are preferable; asubstituted or unsubstituted cycloalkenyl group, a substituted orunsubstituted aryl group, and a substituted or unsubstituted heteroarylgroup are particularly preferable. Of these, a substituted phenyl group,a substituted cyclopentenyl group, a substituted cyclohexenyl group, anda substituted thienyl group are preferable, a substituted phenyl group,a substituted cyclopentenyl group and a substituted cyclohexenyl groupare particularly preferable.

As the substituent of the group for R4, a halogen atom (particularly achlorine atom, a bromine atom) and a substituted or unsubstituted loweralkyl group are preferable, and a chlorine atom and a bromine atom areparticularly preferable.

As R5 in formula II, a hydrogen atom and a substituted or unsubstitutedlower alkyl group are preferable. Of these, a substituted orunsubstituted lower alkyl group (particularly a methyl group) isparticularly preferable.

As R6 in formula II, a hydrogen atom and a substituted or unsubstitutedlower alkyl group are preferable. Of these, a hydrogen atom isparticularly preferable.

As the compound of the present invention represented by formula I(hereinafter to be simply referred to as the compound of the presentinvention), the following compounds are preferable.

(Compound A-1)

In formula I, a compound wherein

R1 is as defined above,R2 is any of a hydrogen atom, a substituted or unsubstituted lower alkylgroup, a substituted or unsubstituted aralkyl group, and a hydroxylgroup, andR3 is a group represented by the following formula II:

wherein

R4 is any of a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstitutedcycloalkenyl group, a substituted or unsubstituted aryl group, asubstituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, a halogen atom, a substituted orunsubstituted alkoxy group, a substituted or unsubstituted aryloxygroup, a substituted or unsubstituted heteroaryloxy group, a substitutedor unsubstituted alkylthio group, a substituted or unsubstitutedarylthio group, a substituted or unsubstituted heteroarylthio group, asubstituted or unsubstituted alkylamino group, a substituted orunsubstituted dialkylamino group, a substituted or unsubstitutedarylamino group, a substituted or unsubstituted heteroarylamino group,and an amino group optionally substituted by amino-protecting group(s),andR5 and R6 may be the same or different and each is any of a hydrogenatom and a substituted or unsubstituted lower alkyl group, or R5 and R6optionally form, together with the carbon atom bonded thereto, a 3- to8-membered ring.

Of the compounds A-1, the following Compound A-2 is preferable.

(Compound A-2)

A compound wherein the substituent of the group for R1 is any of a cyanogroup and a group represented by the following formula III:

Z-Y-X-  formula III

wherein each symbol is as defined above,

R2 is any of a hydrogen atom, a substituted or unsubstituted lower alkylgroup, and a substituted or unsubstituted aralkyl group,R4 is any of a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstitutedcycloalkenyl group, a substituted or unsubstituted aryl group, asubstituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, and a halogen atom, andR5 and R6 may be the same or different and each is any of a hydrogenatom and a substituted or unsubstituted lower alkyl group.

Of compounds A-2, the following Compound A-3 is preferable.

(Compound A-3)

A compound wherein

R1 is any of a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, and a substituted or unsubstitutedaralkyl group.

Of compounds A-2, the following Compound A-4 is also preferable.

(Compound A-4)

A compound wherein

R1 is any of a substituted or unsubstituted aryl group, a substituted orunsubstituted heteroaryl group, a substituted or unsubstitutedheterocyclic group, a substituted or unsubstituted cycloalkyl group, anda substituted or unsubstituted cycloalkenyl group,

-   -   wherein the substituent of the group for R1 is a group        represented by the following formula III:

Z-Y-X-  formula III

-   -    wherein each symbol is as defined above,        R2 is a hydrogen atom,        R4 is any of a substituted or unsubstituted aryl group, a        substituted or unsubstituted heteroaryl group, a substituted or        unsubstituted heterocyclic group, a substituted or unsubstituted        cycloalkyl group, and a substituted or unsubstituted        cycloalkenyl group,        R5 is a substituted or unsubstituted lower alkyl group, and        R6 is a hydrogen atom.

Of compounds A-4, the following Compound A-5 is preferable.

(Compound A-5)

A compound

wherein R4 is a substituted or unsubstituted cycloalkenyl group.

Of compounds A-4, the following Compound A-6 is also preferable.

(Compound A-6)

A compound wherein

ring A is any of ring-1 and ring-2,R1 is a substituted phenyl group,X is any of a substituted or unsubstituted methylene group, asubstituted or unsubstituted ethylene group, and a substituted orunsubstituted vinylene group,Y is any of a sulfur atom, a sulfonyl group, a substituted orunsubstituted methylene group, and an oxygen atom,Z is any of a substituted methyl group, a substituted ethyl group, asubstituted propyl group, and a substituted carbamoyl group,

-   -   wherein the substituent of the group for Z is any of a carboxyl        group, a carboxylic acid ester group, an acetylamino group, a        sulfonic acid group, and a hydroxyl group, and the group for Z        optionally has multiple substituents selected from the        substituents,        R4 is any of a substituted phenyl group, a substituted        cyclopentenyl group, a substituted cyclohexenyl group, and a        substituted thienyl group,    -   wherein the substituent of the group for R4 is any of a chlorine        atom, a bromine atom, and a substituted or unsubstituted lower        alkyl group, and        R5 is a methyl group.

Of compounds Compound A-6, the following Compound A-7 is preferable.

(Compound A-7)

A compound wherein

X is any of a methylene group, a ethylene group, and a vinylene group,Y is any of a sulfur atom, a sulfonyl group, a methylene group, and anoxygen atom,Z is any of a substituted methyl group, a substituted ethyl group, asubstituted propyl group, and a substituted carbamoyl group,

-   -   wherein the substituent of the group for Z is any of a carboxyl        group, a carboxylic acid ester group, an acetylamino group, and        a sulfonic acid group, and the group for Z optionally has        multiple substituents selected from the substituents,        R4 is any of a substituted phenyl group, a substituted        cyclopentenyl group, and a substituted cyclohexenyl group,    -   wherein the substituent of the group for R4 is any of a chlorine        atom and a bromine atom.

As the compound of the present invention, the following Compound B-1 isalso preferable.

(Compound B-1)

In formula I, a compound wherein

R1 is any of a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, a halogen atom, a substituted orunsubstituted alkoxy group, a substituted or unsubstituted aryloxygroup, a substituted or unsubstituted heteroaryloxy group, a substitutedor unsubstituted alkylthio group, a substituted or unsubstitutedarylthio group, a substituted or unsubstituted heteroarylthio group, asubstituted or unsubstituted alkylamino group, a substituted orunsubstituted dialkylamino group, a substituted or unsubstitutedcycloalkylamino group, a substituted or unsubstituted dicycloalkylaminogroup, a substituted or unsubstituted arylamino group, a substituted orunsubstituted heteroarylamino group, a substituted or unsubstitutedalkanoyl group, a substituted or unsubstituted carboxylic acid estergroup, a substituted or unsubstituted carbamoyl group, and an aminogroup optionally substituted by amino-protecting group(s), andR4 is any of a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, a halogen atom, a substituted orunsubstituted alkoxy group, a substituted or unsubstituted aryloxygroup, a substituted or unsubstituted heteroaryloxy group, a substitutedor unsubstituted alkylthio group, a substituted or unsubstitutedarylthio group, a substituted or unsubstituted heteroarylthio group, asubstituted or unsubstituted alkylamino group, a substituted orunsubstituted dialkylamino group, a substituted or unsubstitutedcycloalkylamino group, a substituted or unsubstituted dicycloalkylaminogroup, a substituted or unsubstituted arylamino group, a substituted orunsubstituted heteroarylamino group, and an amino group optionallysubstituted by amino-protecting group(s).

Of Compounds B-1, the following Compound B-2 is preferable.

(Compound B-2)

A compound wherein

R1 is a substituted phenyl group,

-   -   wherein the substituent of the group for R1 is any of a cyano        group and a group represented by the following formula III:

Z-Y-X-  formula III

-   -    wherein        -   X is any of a methylene group and an ethylene group,        -   Y is any of a sulfur atom, a sulfinyl group, a sulfonyl            group, an oxygen atom, a substituted or unsubstituted amino            group, and a methylene group, and        -   Z is any of a substituted or unsubstituted lower alkyl            group, a substituted or unsubstituted lower alkenyl group, a            substituted or unsubstituted alkanoyl group, a substituted            or unsubstituted triazole group, and a substituted or            unsubstituted tetrazole group,            -   wherein the substituent of the group for Z is any of a                carboxyl group, an alkoxycarbonyl group, a furyl group,                a phenyl group, a hydroxyl group, a carbamoyl group, a                carbamoyl group substituted by lower alkyl group(s), a                carbamoyl group substituted by carboxy lower alkyl                group(s), a carbamoyl group substituted by lower alkyl                group(s) substituted by a furyl group, an amino group                optionally substituted by amino-protecting group(s), a                sulfonic acid group, a pyrrolylcarbonyl group, a pyridyl                group, and a halogen atom, and the group for Z                optionally has the same or different multiple                substituents selected from the substituents,                R2 is a hydrogen atom,                R3 is a group represented by the following formula II:

-   -   wherein        R4 is a substituted or unsubstituted phenyl group,    -   wherein the substituent of the group for R4 is a halogen atom,        R5 is any of a hydrogen atom, a lower alkyl group, and a lower        alkyl group substituted by 1 to 3 halogen atoms, and        R6 is a hydrogen atom.

Of compounds A-1, the following Compound B-3 is also preferable.

(Compound B-3)

A compound wherein

R1 is any of a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, a halogen atom, a substituted orunsubstituted alkoxy group, a substituted or unsubstituted aryloxygroup, a substituted or unsubstituted heteroaryloxy group, a substitutedor unsubstituted alkylthio group, a substituted or unsubstitutedarylthio group, a substituted or unsubstituted heteroarylthio group, asubstituted or unsubstituted alkylamino group, a substituted orunsubstituted dialkylamino group, a substituted or unsubstitutedcycloalkylamino group, a substituted or unsubstituted dicycloalkylaminogroup, a substituted or unsubstituted arylamino group, a substituted orunsubstituted heteroarylamino group, a substituted or unsubstitutedalkanoyl group, a substituted or unsubstituted carboxylic acid estergroup, a substituted or unsubstituted carbamoyl group, and an aminogroup optionally substituted by amino-protecting group(s),R4 is any of a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, a halogen atom, a substituted orunsubstituted alkoxy group, a substituted or unsubstituted aryloxygroup, a substituted or unsubstituted heteroaryloxy group, a substitutedor unsubstituted alkylthio group, a substituted or unsubstitutedarylthio group, a substituted or unsubstituted heteroarylthio group, asubstituted or unsubstituted alkylamino group, a substituted orunsubstituted dialkylamino group, a substituted or unsubstitutedarylamino group, a substituted or unsubstituted heteroarylamino group,and an amino group optionally substituted by amino-protecting group(s).

Of compounds A-2, the following Compound B4 is preferable.

(Compound B-4)

In formula I, a compound wherein

R1 is any of a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, a halogen atom, a substituted orunsubstituted alkoxy group, a substituted or unsubstituted aryloxygroup, a substituted or unsubstituted heteroaryloxy group, a substitutedor unsubstituted alkylthio group, a substituted or unsubstitutedarylthio group, a substituted or unsubstituted heteroarylthio group, asubstituted or unsubstituted alkylamino group, a substituted orunsubstituted dialkylamino group, a substituted or unsubstitutedcycloalkylamino group, a substituted or unsubstituted dicycloalkylaminogroup, a substituted or unsubstituted arylamino group, a substituted orunsubstituted heteroarylamino group, a substituted or unsubstitutedalkanoyl group, a substituted or unsubstituted carboxylic acid estergroup, a substituted or unsubstituted carbamoyl group, and an aminogroup optionally substituted by amino-protecting group(s), andR4 is any of a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, and a halogen atom.

Of compounds B-4, the following Compound B-5 is preferable.

(Compound B-5)

A compound wherein

R1 is any of a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, and a substituted or unsubstitutedaralkyl group.

Of compounds A-1, the following Compound C-1 is preferable.

(Compound C-1)

In formula I, a compound wherein

the substituent of the group for R1 is any of a hydroxyl group and agroup represented by the following formula III:

Z-Y-X-  formula III

-   -   wherein    -   X is any of an oxygen atom, a substituted or unsubstituted amino        group, a sulfur atom, and a bond,    -   Y is any of a carbonyl group, a sulfonyl group, and a bond, and    -   Z is any of a substituted or unsubstituted alkyl group, a        substituted or unsubstituted alkenyl group, a substituted or        unsubstituted alkynyl group, a substituted or unsubstituted        alkanoyl group, a substituted or unsubstituted aryl group, a        substituted or unsubstituted heteroaryl group, a substituted or        unsubstituted heterocyclic group, a substituted or unsubstituted        alkoxy group, a substituted or unsubstituted aryloxy group, a        substituted or unsubstituted heteroaryloxy group, a substituted        or unsubstituted alkylthio group, a substituted or unsubstituted        arylthio group, a substituted or unsubstituted heteroarylthio        group, a substituted or unsubstituted alkylamino group, a        substituted or unsubstituted dialkylamino group, a substituted        or unsubstituted cycloalkylamino group, a substituted or        unsubstituted dicycloalkylamino group, a substituted or        unsubstituted arylamino group, and a substituted or        unsubstituted heteroarylamino group,        -   wherein the substituent of the group for Z is any of a lower            alkyl group, a carboxyl group, a carboxylic acid ester            group, a substituted or unsubstituted alkanoyloxy group, a            substituted or unsubstituted carbamoyl group, a cyano group,            a hydroxyl group, a sulfonic acid group, a sulfonamido            group, a phosphoric acid group, a phosphoric acid monoester            group, a phosphoric acid diester group, an amino group            optionally substituted by amino-protecting group(s), a thiol            group, a halogen atom, a substituted or unsubstituted aryl            group, a substituted or unsubstituted heteroaryl group, a            substituted or unsubstituted heterocyclic group, a            substituted or unsubstituted alkanoyl group, a substituted            or unsubstituted arylcarbonyl group, and a substituted or            unsubstituted heteroarylcarbonyl group, and the group for Z            optionally has the same or different multiple substituents            selected from the substituents,            R2 is any of a hydrogen atom, a substituted or unsubstituted            lower alkyl group, and a substituted or unsubstituted            aralkyl group,            R4 is any of a substituted or unsubstituted alkyl group, a            substituted or unsubstituted cycloalkyl group, a substituted            or unsubstituted cycloalkenyl group, a substituted or            unsubstituted aryl group, a substituted or unsubstituted            heteroaryl group, a substituted or unsubstituted            heterocyclic group, a substituted or unsubstituted aralkyl            group, a substituted or unsubstituted alkenyl group, a            substituted or unsubstituted alkynyl group, and a halogen            atom, and            R5 and R6 may be the same or different and each is any of a            hydrogen atom and a substituted or unsubstituted lower alkyl            group.

Of compounds C-1, the following Compound C-2 is preferable.

(Compound C-2)

In formula I, a compound wherein

R1 is any of a substituted or unsubstituted phenyl group, a substitutedor unsubstituted heteroaryl group, a substituted or unsubstitutedheterocyclic group, a substituted or unsubstituted cycloalkyl group, anda substituted or unsubstituted cycloalkenyl group,

-   -   wherein the substituent of the group for R1 is any of a hydroxyl        group and a group represented by the following formula III:

Z-Y-X-  formula III

-   -    wherein        -   X is any of an oxygen atom, a substituted or unsubstituted            amino group, a sulfur atom, and a bond,        -   Y is any of a carbonyl group, a sulfonyl group, and a bond,            and        -   Z is a substituted or unsubstituted allyl group            -   wherein the substituent of the group for Z is any of a                lower alkyl group, a carboxyl group, a carboxylic acid                ester group, a substituted or unsubstituted alkanoyloxy                group, a substituted or unsubstituted carbamoyl group, a                cyano group, a hydroxyl group, a sulfonic acid group, a                sulfonamido group, a phosphoric acid group, a phosphoric                acid monoester group, a phosphoric acid diester group,                an amino group optionally substituted by                amino-protecting group(s), a thiol group, a halogen                atom, a substituted or unsubstituted aryl group, a                substituted or unsubstituted heteroaryl group, a                substituted or unsubstituted heterocyclic group, a                substituted or unsubstituted alkanoyl group, a                substituted or unsubstituted arylcarbonyl group, and a                substituted or unsubstituted heteroarylcarbonyl group,                and the group for Z optionally has the same or different                multiple substituents selected from the substituents.

Of compounds C-2, the following Compound C-3 is preferable.

(Compound C-3)

In formula I, a compound wherein

ring A is any of ring-1 and ring-2, andR1 is a substituted phenyl group,

-   -   wherein the substituent of the group for R1 is any of a hydroxyl        group and a group represented by the following formula III:

Z-Y-X-  formula III

-   -    wherein        -   X is any of an oxygen atom and a substituted or            unsubstituted amino group,        -   Y is any of a carbonyl group, and a bond, and        -   Z is a substituted or unsubstituted alkyl group,            -   wherein the substituent of the group for Z is any of a                lower alkyl group, a carboxyl group, a carboxylic acid                ester group, a substituted or unsubstituted alkanoyloxy                group, a substituted or unsubstituted carbamoyl group, a                cyano group, a hydroxyl group, a sulfonic acid group, a                sulfonamido group, a phosphoric acid group, a phosphoric                acid monoester group, a phosphoric acid diester group,                an amino group optionally substituted by                amino-protecting group(s), a thiol group, a halogen                atom, a substituted or unsubstituted aryl group, a                substituted or unsubstituted heteroaryl group, a                substituted or unsubstituted heterocyclic group, a                substituted or unsubstituted alkanoyl group, a                substituted or unsubstituted arylcarbonyl group, and a                substituted or unsubstituted heteroarylcarbonyl group,                and the group for Z optionally has the same or different                multiple substituents selected from the substituents.

Of Compounds C-3, the following Compound C-4 is preferable.

(Compound C-4)

In formula I, a compound wherein

the substituent of the group for R1 is any of a hydroxyl group and agroup represented by the following formula III:

Z-Y-X-  formula III

-   -   wherein    -   X is any of an oxygen atom and a substituted or unsubstituted        amino group,    -   Y is any of a carbonyl group and a bond,    -   Z is a substituted or unsubstituted alkyl group,        -   wherein the substituent of the group for Z is any of a lower            alkyl group, a carboxyl group, a carboxylic acid ester            group, alkanoyloxy group, a hydroxyl group, a sulfonic acid            group, and an amino group optionally substituted by            amino-protecting group(s), and the group for Z optionally            has the same or different multiple substituents selected            from the substituents.

Particularly preferable compound of the present invention is,

-   methyl    3-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}-benzylsulfanyl)propionate    (Compound 1);-   3-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)propionic    acid (Compound 2);-   3-(4-{4-[(1R)-1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)-propionic    acid (Compound 3);-   N-acetyl-S-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzyl)-L-cysteine    (Compound 4);-   2-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)-ethanesulfonic    acid (Compound 5);-   3-(4-{4-[(1R)-1-(2-bromophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)-propionic    acid (Compound 6);-   N-acetyl-S-(4-{4-[(1R)-1-(2-bromophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzyl)-L-cysteine    (Compound 7);-   3-(4-{4-[1-(2-chloro-1-cyclopentenyl)ethoxycarbonylamino]-3-isoxazolyl}-benzylsulfanyl)propionic    acid (Compound 8);-   3-(4-{4-[(1R)-1-(2-chloro-1    cyclopentenyl)ethoxycarbonylamino]-3-isoxazolyl}-benzylsulfanyl)propionic    acid (Compound 9);-   3-(4-{4-[1-(2-chloro-1-cyclohexenyl)ethoxycarbonylamino]-3-isoxazolyl}-benzylsulfanyl)propionic    acid (Compound 10);-   3-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfonyl)-propionic    acid (Compound 11);-   3-(4-{4-[(1R)-1-(2-bromophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfonyl)-propionic    acid (Compound 12);-   3-(4-{4-[1-(2-chloro-1-cyclohexenyl)ethoxycarbonylamino]-3-isoxazolyl}-benzylsulfonyl)propionic    acid (Compound 13);-   {[2-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)ethyl]thio}-acetic    acid (Compound 14);-   {3-[2-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)ethyl]thio}-propionic    acid (Compound 15);-   {[2-(4-{4-[1-(2-chlorocyclopentenyl)ethoxycarbonylamino]-3-isoxazolyl}-phenyl)ethyl]thio}acetic    acid (Compound 16);-   {[2-(4-{4-[1-(2-chlorocyclohexenyl)ethoxycarbonylamino]-3-isoxazolyl}-phenyl)ethyl]thio}acetic    acid (Compound 17);-   3-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-5-isoxazolyl}benzylsulfanyl)propionic    acid (Compound 18);-   5-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)-4-pentanoic    acid (Compound 19);-   3-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}-benzyloxycarbonylamino)propionic    acid (Compound 20);-   4-[(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)amino]-(2R)-2-hydroxy-4-oxobutanoic    acid (Compound 21);-   4-[4-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-isoxazolyl]phenyl    acetate-   (Compound 22);-   1-(2-chlorophenyl)ethyl 3-(4-hydroxyphenyl)-4-isoxazolylcarbamate    (Compound 23);-   5-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenoxy)pentanoic    acid-   (Compound 24);-   4-[(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)amino]-4-oxobutanoic    acid (Compound 25);-   (2R)-2-acetoxy-4-[(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}-phenyl)amino]-4-oxobutanoic    acid (Compound 26);-   {[2-(4-{4-[(1R)-1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}-phenyl)ethyl]thio}acetic    acid (Compound 27);-   3-(4-{4-[(1R)-1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfonyl)-propionic    acid (Compound 28);-   {3-[2-(4-{4-[(1R)-1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}-phenyl)ethyl]thio}propionic    acid (Compound 25);-   5-(4-{4-[(1R)-1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)-4-pentenoic    acid (Compound 30);-   5-(4-{4-[(1R)-1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)-4-pentanoic    acid (Compound 31);-   6-(4-{4-[(1R)-1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)hexanoic    acid (Compound 32);-   5-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)-3,3-dimethylpentanoic    acid (Compound 33); and-   5-(4-{4-[(1R)-1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)-2-methylpentanoic    acid (Compound 34) can be mentioned.

When the compound of the present invention can form a salt, apharmaceutically acceptable salt is preferable. As such pharmaceuticallyacceptable salt, for the acidic group in the formula, such as carboxylgroup and the like, for example, an ammonium salt, salts with alkalimetals such as sodium, potassium, and the like, salts with alkalineearth metals such as calcium, magnesium, and the like, aluminum salt,zinc salt, salts with organic amines such as triethylamine,ethanolamine, morpholine, pyrrolidine, piperidine, piperazine,dicyclohexylamine, and the like, and salts with basic amino acids suchas arginine, lysine, and the like can be mentioned.

For the basic group when a basic group is present in formula I, saltswith inorganic acids such as hydrochloric acid, sulfuric acid,phosphoric acid, nitric acid, hydrobromic acid, and the like, salts withorganic carboxylic acids such as acetic acid, citric acid, benzoic acid,maleic acid, fumaric acid, tartaric acid, succinic acid, tannic acid,butyric acid, hibenzic acid, pamoic acid, enanthic acid, decanoic acid,teoclic acid, salicylic acid, lactic acid, oxalic acid, mandelic acid,malic acid, and the like, and salts with organic sulfonic acids such asmethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, andthe like can be mentioned. As a method for forming a salt, mixing thecompound of the present invention with a necessary acid or base at asuitable amount ratio in a solvent or dispersing agent, or cationexchange or anion exchange of a salt in other form is carried out.

The compound of the present invention includes solvates thereof, such ashydrates, alcohol addition products, and the like.

The compound of the present invention encompasses an optical isomerthereof, a stereoisomer thereof, a regioisomer thereof, a tautomerthereof, a rotational isomer thereof, and mixtures thereof at anoptional ratio, when they are present. These can be each obtained as asingle product by synthesis methods and separation methods known per se.

For example, an optical isomer can be obtained by the use of anoptically active synthetic intermediate, or a racemate of the syntheticintermediate or the final product can be subjected to optical resolutionaccording to a conventional method.

The compound of the present invention can be converted to a prodrug. Inthe present invention, the term prodrug means a compound that isconverted in the body to produce the compound of the present invention.For example, when the active compound contains a carboxyl group or aphosphoric acid group, an ester thereof, an amide thereof, and the likecan be mentioned, and when the active compound contains a carboxylgroup, a group that is converted to a carboxyl group by oxidativemetabolism, such as hydroxymethyl group and the like can be mentioned.In addition, when the active compound contains an amino group, an amidethereof, a carbamate thereof, and the like can be mentioned. When theactive compound contains a hydroxyl group, an ester thereof, a carbonatethereof, a carbamate thereof, and the like can be mentioned. When thecompound of the present invention is converted to a prodrug, it may bebonded to amino acid or sugars.

The metabolite in the present invention is a compound obtained byconversion of the compound of the present invention due to a metabolicenzyme and the like in the living organisms. For example, a compoundwherein a hydroxyl group has been introduced by metabolism onto thebenzene ring of the compound of the present invention, a compoundwherein an alkoxy group of the compound of the present invention hasbeen converted to a hydroxyl group by metabolism, a compound wherein anN!O bond of the isoxazole ring of the compound of the present inventionhas been cleaved by metabolism, and the like can be mentioned. Inaddition, a compound wherein a carboxylic acid moiety of the compound ofthe present invention, or a hydroxyl group of the compound of thepresent invention, which has been added by metabolism, is bonded toglucuronic acid, glucose, or amino acid and the like can be mentioned.

Since the compounds of the present invention and pharmaceuticallyacceptable salts thereof (hereinafter to be simply referred to as thecompounds of the present invention) have low toxicity and inhibit thephysiological activity of LPA, they can be used as pharmaceuticalagents. For example, they can be used as agents for the prophylaxis ortreatment of diseases in which inhibition of the physiological activityof LPA is useful for the prophylaxis or treatment thereof (disease inwhich LPA receptor participates, and the like). More specifically, theycan be used as agents for the prophylaxis or treatment of fibrosis oforgans (liver, kidney, lung, and the like), hepatic disease (acute andchronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension,regenerative failure, non-alcoholic steatohepatitis (NASH), liverhypofunction, hepatic blood flow disorder, and the like), cellproliferative disease (cancer (solid tumor, solid tumor metastasis,vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia,and the like) and invasive metastasis of cancer cell and the like),inflammatory disease (psoriasis, nephropathy, pneumonia, and the like),gastrointestinal tract disease (irritable bowel syndrome (IBS),inflammatory bowel disease (IBD), abnormal pancreatic secretion, and thelike), renal disease, urinary tract-associated disease (benign prostatichyperplasia or symptoms associated with neuropathic bladder disease,spinal cord tumor, hernia of intervertebral disk, spinal canal stenosis,symptoms derived from diabetes, lower urinary tract disease (obstructionof lower urinary tract and the like), inflammatory disease of lowerurinary tract, dysuria, frequent urination, and the like), pancreasdisease, abnormal angiogenesis-associated disease (arterial obstructionand the like), brain-associated disease (cerebral infarction, cerebralhemorrhage, and the like) or peripheral neuropathy, and the like.Particularly, they can be used as agents for the prophylaxis ortreatment of fibrosis of organs (liver, kidney, lung, and the like) orliver diseases.

The compounds of the present invention and salts thereof can beadministered as they are, or as a pharmaceutical composition containingvarious pharmaceutically acceptable carriers according to a method knownper se, orally or parenterally (e.g., routes via intravenous,subcutaneous, intramuscular, suppository, intestinal infusion, ointment,plaster, sublingual, instillation, inhalation, etc.) to a mammal (human,mouse, rat, rabbit, dog, cat, bovine, pig, monkey, etc.). While the dosefor the above-mentioned object is determined depending on the objectivetreatment effect, administration method, treatment period, age, bodyweight, and the like, when an oral or parenteral route is employed, thedaily dose for an adult is generally 1 μg to 10 g by oraladministration, and 0.01 μg to 1 g by parenteral administration. Thecontent of the compound of the present invention in the above-mentionedpharmaceutical composition is about 0.01 wt % to 100 wt % of the wholecomposition.

As a pharmaceutically acceptable carrier for the pharmaceuticalcomposition of the present invention, various organic or inorganiccarrier substances conventionally used as materials for preparation canbe mentioned. For example, excipients, lubricants, binders,disintegrants, water-soluble polymers, basic inorganic salts for solidpreparations; solvents, dissolution aids, suspending agents, isotonicityagents, buffers, soothing agents, and the like for liquid preparationscan be mentioned. Where necessary, general additives, such aspreservatives, antioxidants, coloring agents, sweetening agents, souringagents, bubbling agents, flavors, and the like can also be used.

As the dosage form of such pharmaceutical compositions, for example,tablets, powders, pills, granules, capsules, suppositories, liquids,sugar coatings, depots, syrups, suspensions, emulsions, troches,sublingual tablets, adhesive agents, intraorally disintegrants(tablets), inhalants, intestinal infusions, ointments, plasters, tapes,and eye drops can be mentioned, and a pharmaceutical composition can beproduced using ordinary preparation auxiliaries and according to aconventional method.

The pharmaceutical composition of the present invention can be producedaccording to a method conventionally used in the technical field ofpreparations, such as a method described, for example, in the JapanesePharmacopoeia and the like. Concrete production methods of thepreparation are described in detail in the following.

For example, when the compound of the present invention is formed as anoral preparation, an excipient, and where necessary, a binder,disintegrant, lubricant, coloring agent, flavoring agent, and the likeare added, and the mixture is processed according to a conventionalmethod to give, for example, a tablet, powder, pill, granule, capsule,suppository, solution, sugar coating agent, depot, syrup, and the like.As the excipient, for example, lactose, cornstarch, sucrose, glucose,sorbit, crystalline cellulose, and the like can be used, as the binder,for example, polyvinyl alcohol, polyvinyl ether, ethylcellulose,methylcellulose, gum arabic, tragacanth, gelatin, shellac,hydroxypropylcellulose, hydroxypropyl starch, polyvinylpyrrolidone, andthe like can be used, as the disintegrant, for example, starch, agar,gelatin powder, crystalline cellulose, calcium carbonate, sodiumhydrogencarbonate, calcium citrate, dextran, pectin, and the like can beused, as the lubricant, for example, magnesium stearate, talc,polyethylene glycol, silica, hydrogenated vegetable oil, and the likecan be used, as the coloring agent, those permitted to be added topharmaceutical products can be used, and as the flavoring agent, cocoapowder, menthol, aromatic powder, mentha oil, borneo camphor, powderedcinnamon bark, and the like are used. It is naturally permissible toappropriately apply a sugar coating, gelatin coating, and othernecessary coating to these tablets and granules.

When an injection is to be prepared, a pH adjusting agent, buffer,stabilizer, preservative, and the like are added where necessary, andthe mixture is processed according to a conventional method to give asubcutaneous, intramuscular, or intravenous injection.

The compound of the present invention can be used appropriately alongwith one or more other pharmaceutical agents depending on the desiredobject. For example, when the compound of the present invention is usedfor liver fibrosis, it can be used for the treatment concurrently withcommercially available drugs for liver diseases, such as interferon,glycyrrhizin, and Urso™. In the case of concurrent use, the dose thereofis appropriately determined according to the kind and efficacy of thepharmaceutical agent to be concurrently used, administration method,treatment period, age, body weight, and the like.

While the production methods of the compounds of the present inventionare explained in the following, the production methods of the compoundsof the present invention are not limited to those mentioned below. Inaddition, the functional groups other than the reaction site may beprotected in advance as necessary before carrying out thebelow-mentioned reactions and deprotected at a suitable stage. In eachstep, moreover, the reaction may be carried out according to the methodsgenerally employed, and isolation and purification can be performed by amethod conventionally employed, such as crystallization,recrystallization, column chromatography, thin layer chromatography,preparative HPLC, and the like, which are selected as appropriate orused in combination.

The symbols used for the explanation of the production methods are shownin the following. Each symbol is as defined above unless otherwisespecified.

R′=carbamate group, carboxylic acid ester group, and the like,R″, R′″=group forming carboxylate (lower alkyl group such as methylgroup, ethyl group, and the like, etc.), andX=halogen atom (fluorine atom, chlorine atom, bromine atom, and iodineatom)

As shown in the following schemes, compound (I-1) encompassed in thecompound of the present invention can be produced by Curtius reaction(reaction A) from carboxylic acid, Hofmann reaction (reaction B)according to a reference (J. Org. Chem., 1993, vol. 58, p. 2478 andreferences cited in this reference), rearrangement reaction (reaction C)according to a reference (J. Heterocyclic. Chem., 1972, 837 and J.Heterocyclic. Chem., 1972, 577), and the like. Furthermore, theoptically active final compound can be produced using an opticallyactive alcohol (R3OH) to be used for these reactions.

Azolecarboxylic acid, diazolecarboxylic acid, and their esters to beused as starting materials can be produced according to known methodsshown below.

1. General Production Methods of Isoxazolecarboxylate andIsoxazolecarboxylic Acid.

Isoxazolecarboxylate represented by formula (b) can be produced by amethod similar to the method described in WO0240458, which is shown inthe following scheme. To be specific, the 1,3-dicarbonyl compoundobtained by reacting a ketone with a dialkyl carbonate is reacted withN,N-dimethylformamide dimethylacetal to give hydroxyacrylate. Thiscompound is further treated with hydroxylamine hydrochloride to giveisoxazolecarboxylate represented by formula (b).

In addition, isoxazolecarboxylate represented by formula (c) can beproduced according to a method described in J. Heterocyclic. Chem.,2000, vol. 37, p. 75, which is shown in the following scheme. To bespecific, a vinyl ester obtained by reacting propargylate withp-nitrobenzoic acid in the presence of a suitable base (e.g.,N-methylmorpholine and the like) is reacted with a chlorooxime formobtained by treating oxime with a suitable chlorinating reagent (e.g.,N-chlorosuccinimide and the like) to give isoxazolecarboxylaterepresented by formula (c).

The isoxazolecarboxylate (formula (c)) can also be produced by a methodsimilar to the method described in Bull. Chem. Soc. Jpn., 1999, vol.72(10), p. 2277. To be specific, an oximecarboxylic acid is reacted withpropargylate in the presence of cerium (IV) ammonium nitrate (CAN) togive isoxazolecarboxylate.

The isoxazolecarboxylate (formula (c)) can also be produced by a methodsimilar to the method described WO9828282. To be specific, an oxime isconverted to chlorooxime with N-chlorosuccinimide and then reacted withvinyl carboxylate to give the isoxazolecarboxylate represented byformula (c).

2. General Production Methods of Isothiazolecarboxylate andIsothiazolecarboxylic Acid.

Isothiazolecarboxylic acid represented by formula (d) can be produced bya method similar to the method described in Bull. Chem. Soc. Jpn., 1968,vol. 41, p. 965, which is shown in the following scheme. To be specific,a suitable nitrile is reacted with n-propionitrile in the presence ofsodium, and the resulting imine is further reacted with thionyl chlorideto give isothiazolenitrile. This compound is treated with concentratedsulfuric acid and sodium sulfite to give the isothiazolecarboxylic acidrepresented by formula (d).

Isothiazolecarboxylate represented by formula (e) can be produced by aknown method shown in the following scheme. That is, according to themethod described in U.S. Pat. No. 5,087,631, α-bromocarboxylic acid isreacted with potassium thioacetate and the resultingα-thioacetylcarboxylic acid is treated with ammonia to giveα-mercaptocarboxylic acid. This compound is further treated with t-butylnitrite and then dicyclohexylcarbodiimide (DCC) to give 5-membered ringcompound (f), which is reacted with propargylate by a method similar tothe method described in Tetrahedron Lett., 1971, vol. 12(17), p. 1281,to give the isothiazolecarboxylate represented by formula (e).

Isothiazolecarboxylate represented by formula (e) can also be producedby a method similar to the method described in Tetrahedron Lett., 1971,vol. 12(17), p. 1281, which is shown in the following scheme. The5-membered ring compound (f) obtained by the above-mentioned method isreacted with acetylenedicarboxylate to give isothiazoledicarboxylate,which is subjected to hydrolysis, and then decarboxylation reaction togive the isothiazolecarboxylic acid represented by formula (e).

The 5-membered ring compound (f) used here can also be producedaccording to a method described in Chem. Ber., 1972, vol. 105, p. 188,which is shown in the following scheme. To be specific,α-hydroxycarboxylic acid is reacted with thionyl chloride to givea-chlorocarboxylic acid, which is then reacted with hydrogen sulfide inthe presence of a base to give α-mercaptocarboxylic acid. This compoundis reacted with ethyl nitrite and dicyclohexylcarbodiimide (DCC) to givethe 5-membered ring compound represented by formula (f).

3. General Production Methods of Oxadiazolecarboxylate andOxadiazolcarboxylic Acid.

1,2,3-Oxadiazolecarboxylate represented by formula (g) can be producedby a known method shown in the following scheme. To be specific, theoxime form obtained by treating β-ketocarboxylate with sodium nitrite inthe presence of acetic acid by a method similar to the method describedin J. Am. Chem. Soc. 1938, vol. 60, p. 1328, is reduced by a methodsimilar to the method described in Chem. Ber., 1903, vol. 36, p. 3612,to give the amine form. This compound is treated with nitrous acid by amethod similar to the method described in Chem. Ber., 1903, vol. 36, p.3612, to give the 1,2,3-oxadiazolecarboxylate represented by formula(g).

1,2,5-Oxadiazolecarboxylic acid represented by formula (h) can beproduced by a known method shown in the following scheme. To bespecific, a cyanomethylketone form is treated with sodium nitrite inacetic acid by a method similar to the method described EP 0 389 189 togive the oxime form. This compound is further reacted with hydroxylaminehydrochloride in an aqueous sodium hydroxide solution by a methodsimilar to the method described in Gazz. Chim. Ital., 1931, vol. 61, p.943, to give the isoxazolone represented by formula (V). This compoundis treated with sodium carbonate by a method similar to the methoddescribed in Chem. Ber., 1892, vol. 25, p. 2142, to give the1,2,5-oxadiazolecarboxylic acid represented by formula (h).

4. General Production Methods of N-oxy-oxadiazolecarboxylate andN-oxy-oxadiazolecarboxylic Acid.

N-Oxy-1,2,5-oxadiazolecarboxylic acid represented by formula (I-a,b) canbe produced by a method similar to the method described in Liebigs Ann.Chem. 1991, 1211), which is shown in the following scheme. To bespecific, a substituted allyl alcohol is reacted with sodium nitrite inacetic acid to give the N-oxy-1,2,5-oxadiazolylmethanol (J-a).

This compound is subjected to Jones oxidization to give theN-oxy-1,2,5-oxadiazolecarboxylic acid represented by formula (I-a). Inaddition, by heating the N-oxy-1,2,5-oxadiazolylmethanol represented byformula (J-a) in a solvent, the N-oxy-1,2,5-oxadiazolylmethanolrepresented by formula (J-b) can be produced. This compound is furthersubjected to Jones oxidization to give theN-oxy-1,2,5-oxadiazolecarboxylic acid represented by formula (I-b).

N-Oxy-1,2,5-oxadiazolecarboxylate represented by formula (K-a, b) canalso be produced by a method similar to the method described in Chem.Ber. 1895, vol. 28, p. 2675 or J. Heterocyclic. Chem., 1972, 577, whichis shown in the following scheme. By treating the dioxime form withnitrous acid to give the N-oxy-1,2,5-oxadiazolecarboxylate representedby formula (K-b). This compound is heated in a solvent to give theN-oxy-1,2,5-oxadiazolecarboxylate represented by formula (K-a).

N-Oxy-1,2,5-oxadiazolecarboxylic acid represented by formula (I-a) canalso be produced by a method similar to the method described in Liebigs.Ann. Chem., 1990, 335, which is shown in the following scheme. To bespecific, the isoxazolone represented by formula (V) is treated withpotassium hypochlorite and hydrochloric acid to give theN-oxy-1,2,5-oxadiazolecarboxylic acid represented by formula (I-a).

5. General Production Methods of Thiadiazolecarboxylate andThiadiazolecarboxylic Acid.

1,2,3-Thiadiazolecarboxylic acid represented by formula (L) can beproduced by a known method shown in the following scheme. To bespecific, an acylhydrazone is treated with thionyl chloride by a methodsimilar to the method described in Can. J. Chem., 1968, vol. 46, p.1057, to give a 1,2,3-thiadiazole. This compound is treated with carbondioxide in the presence of methyl lithium by a method similar to themethod described in Synthesis. 1985, 945, to give the1,2,3-thiadiazolecarboxylic acid represented by formula (L).

1,2,3-Thiadiazolecarboxylate represented by formula (M) can be producedby a method similar to the method described in Chem. Ber 1916, vol. 49,p. 1978, which is shown in the following scheme. To be specific, adiazoacetate is treated with a carbonyl halide to give a diazoketone,which is further treated with hydrogen sulfide to give the1,2,3-thiadiazolecarboxylate represented by formula (M).

In addition, 1,2,3-thiadiazolecarboxylic acid represented by formula (L)can also be produced by a method similar to the method described inAnnalen, 1904, vol. 333, p. 4, which is shown in the following scheme.To be specific, the 1,2,3-oxadiazolecarboxylic acid produced by theaforementioned method is reacted with ammonium sulfide to give the1,2,3-thiodiazolecarboxylic acid represented by formula (L).

1,2,5-Thiadiazolecarboxylate represented by formula (N) can be producedby a method similar to the method described in J. Heterocyclic. Chem.,1979, 1009, which is shown in the following scheme. To be specific, asubstituted acetylenecarboxylate is treated with tetrasulfurtetranitride to give the 1,2,5-thiadiazolecarboxylate represented byformula (N).

1,2,5-Thiadiazolecarboxylic acid represented by formula (O) can beproduced by a known method shown in the following scheme. To bespecific, a diaminocarboxylic acid produced by a method similar to themethod described in Liebigs Ann. Chem., 1977, 1183, is treated withsulfur chloride by a method similar to the method described in J. Org.Chem., 1967, vol. 32(9), p. 2823, to give 1,2,5-thiadiazolecarboxylicacid represented by formula (O).

1,2,5-Thiadiazolecarboxylate represented by formula (N) can be producedby a method similar to the method described in Heterocycles, 2001, vol.55(1), p. 75, which is shown in the following scheme. To be specific, anα-halooxime form obtained by treating an α-haloketone with hydroxylaminehydrochloride is treated with potassium cyanide to give an isoxazole.This compound is treated with tetrasulfur tetranitride or tetrasulfurtetranitride antimony pentachloride to give a thiadiazolecarboxamide,which is then treated with trifluoroborane to give the1,2,5-thiadiazolecarboxylate represented by formula (N).

6. Others

A compound represented by the following formula (P) can be produced bycondensing compound (R) or (S), wherein Y is a suitable leaving groupsuch as a chloro group, a bromine group, an iodine group, a tosyl group,a mesyl group, and the like, with a suitable nucleophilic agent (T) or(U), wherein Y′ is an oxygen atom, a nitrogen atom, a sulfur atom, or acarbon atom activated with an electron-withdrawing substituent, underbasic conditions. A compound (P) wherein Y′ is a nitrogen atom can alsobe produced by reductive amination reaction and the like, and a compound(P) wherein Y′ is an oxygen atom can also be produced by Mitsunobureaction and the like.

A compound represented by the following formula (I-2) wherein R2 is asubstituted or unsubstituted lower alkyl group, a substituted orunsubstituted aralkyl group and the like, which is encompassed in thecompound of the present invention, can be produced, for example,according to a method described in Chem. Pharm. Bull., 1981, vol. 29(6),p. 1743, by condensing a compound represented by formula (I-1) withcompound (W), (wherein Y is a suitable leaving group such as a chlorogroup, a bromine group, an iodine group, a tosyl group, a mesyl group,and the like), under basic conditions.

Moreover, a compound represented by formula (I-2) can also be producedutilizing the Mitsunobu reaction between a compound represented byformula (I-1) and a suitable alcohol (Z), and the like.

In addition, a compound represented by the following formula (I-3),which is encompassed in the compound of the present invention, can beproduced by a method described in Tetrahedron Lett. 2001, vol. 42, p.755.

Almost in the same manner as in the above-mentioned method described, oradding a method obvious to those skilled in the art, the followingrepresentative examples of the present invention can be synthesized. Ineach structural formula, R1 is any of the substituents shown in Table 1and Table 2, and R3 is any of the substituents shown in Table 3. Thesubstituents of R1 and R3 include optically active forms thereof.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES Example 1 Synthesis of methyl3-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)propionoate(Compound 1)

The title compound was synthesized by the following two methods(Synthesis Methods A or B).

Synthesis Method A. (Step A-1) Synthesis of 2-methoxycarbonylvinyl4-nitrobenzoate

4-Nitrobenzoic acid (10 g, 59.8 mmol) and methyl propargylate (5.5 g,65.8 mmol) were dissolved in acetonitrile (100 ml), 1′-methylmorpholine(3 g, 30 mmol) was added, and the mixture was stirred overnight at 40°C. The reaction mixture was concentrated under reduced pressure, and theresidue was washed with ether to give the title compound (12.6 g, 50.2mmol, 83.9%).

¹H-NMR (300 MHz, CDCl₃) δ=3.80 (3H, s), 5.98 (1H, d, J=12.6 Hz),8.25-8.38 (4H, m), 8.52 (1H, d, J=12.6 Hz).

(Step A-2) Synthesis of 4-methylbenzaldehyde oxime

4-Methylbenzaldehyde (20 g, 166 mmol), hydroxylamine hydrochloride (12.7g, 183 mmol), and sodium acetate (23.1 g, 282 mmol) were dissolved in amixed solvent of ethanol (400 ml) and water (150 ml), and the mixturewas stirred at 80° C. for 2 hours. The reaction mixture was concentratedunder reduced pressure, water was added, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated aqueoussodium chloride solution, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to give the title compound (20.6 g,152 mmol, 91.8%).

¹H-NMR (300 MHz, CDCl₃) δ=2.39 (3H, s), 7.21 (2H, d, J=7.8 Hz), 7.47(2H, d, J=8.4 Hz), 8.05 (1H bs), 8.15 (1H, s).

(Step A-3) Synthesis of methyl 3-p-tolyl-isoxazole-4-carboxylate

N-Chlorosuccinimide (9.87 g, 73.4 mmol) and pyridine (175 mg, 2.2 mmol)were dissolved in chloroform (100 ml), 4-methylbenzaldehyde oxime (10 g,73.4 mmol) was added, and the mixture was stirred until it became clear.A solution of 2-methoxycarbonylvinyl 4-nitrobenzoate (9.22 g, 36.7 mmol)and triethylamine (12.9 g, 128 mmol) in chloroform (180 ml) was slowlyadded dropwise at 0° C. over 2 hours, and the mixture was stirredovernight at room temperature. Saturated aqueous sodiumhydrogencarbonate solution was added, and the mixture was extracted withdichloromethane. The extract was dried over anhydrous sodium sulfate,and the solvent was evaporated under reduced pressure. The residue waspurified by column chromatography (hexane:ethyl acetate=5:95) to givethe title compound (1.56 g, 7.19 mmol, 19.6%).

¹H-NMR (300 MHz, CDCl₃) δ=2.41 (3H, s), 3.83 (3H, s), 7.27 (2H, d, J=9.0Hz), 7.67 (2H, d, J=8.4 Hz), 8.98 (1H, s).

MS (ESI) m/z 218 (M+H)⁺.

(Step A-4) Synthesis of 3-p-tolyl-isoxazole-4-carboxylic Acid

Methyl 3-p-tolyl-isoxazole-4-carboxylate (3.1 g, 14.3 mmol) wasdissolved in THF (50 ml), 2N aqueous lithium hydroxide solution (50 ml)was added, and the mixture was stirred for 4 hours. Then, 1Nhydrochloric acid (150 ml) was added at 0° C., and the mixture wasextracted with ethyl acetate. The extract was dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure togive the title compound (2.89 g, 14.3 nmol, 100%).

¹H-NMR (300 MHz, CDCl₃) δ=2.42 (3H, s), 7.28 (2H, d, J=7.5 Hz), 7.66(2H, d, J=8.1 Hz), 9.09 (1H, s).

MS (ESI) m/z 204 (M+H)⁺.

(Step A-5) Synthesis of 1-(2-chlorophenyl)ethyl(3-p-tolyl-4-isoxazolyl)carbamate

3-p-Tolyl-isoxazole-4-carboxylic acid (2 g, 9.90 mmol),1-(2-chlorophenyl)ethanol (4.65 g, 29.7 mmol), diphenylphosphoryl azide(3.06 g, 11.9 mmol), and triethylamine (1.10 g, 10.9 mmol) weredissolved in toluene (60 ml), and the mixture was stirred at 90° C. for1 hour. Saturated aqueous sodium hydrogencarbonate solution was added,and the mixture was extracted with ethyl acetate. The extract was driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by column chromatography,(hexane:ethyl acetate=80:20-10:90) to give the title compound (2.07 g,5.80 mmol, 58.6%).

¹H-NMR (300 MHz, CDCl₃) δ=1.58 (3H, d, J=6.6 Hz), 2.45 (3H, s), 6.25(1H, q, J=6.6 Hz), 6.41 (1H, s), 7.10-7.60 (8H, m), 8.89 (1H, s).

MS (ESI) m/z 357 (M+H)⁺.

(Step A-6) Synthesis of 1-(2-chlorophenyl)ethyl[3-(4-bromomethylphenyl)-isoxazolyl]carbamate

1-(2-Chlorophenyl)ethyl (3-p-tolyl-4-isoxazolyl)carbamate (2.07 g, 5.80mmol), N-bromosuccinimide (1.55 g, 8.70 mmol), and anhydrous perbenzoicacid (187 mg, 0.58 mmol) were dissolved in benzene (50 ml), and themixture was refluxed overnight. To the reaction mixture was added 20%aqueous sodium thiosulfate solution, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated aqueoussodium chloride solution and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by column chromatography (hexane:ethyl acetate=95:5-85:15) togive the title compound (1.62 g, 3.73 mmol, 64.4%).

¹H-NMR (300 MHz, DMSO-d₆) δ=1.51 (3H, s), 4.77 (2H, s), 6.08 (1H, m),7.15-7.80 (8H, m), 9.12 (1H, s), 9.44 (1H, m).

(Step A-7) Synthesis of methyl3-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)propionate

To a solution of 1-(2-chlorophenyl)ethyl[3-(4-bromomethylphenyl)-isoxazolyl]carbamate (615 mg, 1.41 mmol) indichloromethane (18 ml) were added triethylamine (855 mg, 8.47 mmol) andmethyl 3-mercaptopropionate (445 mg, 4.23 mmol), and the mixture wasstirred overnight at room temperature. Water was added, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium chloride solution and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure, andthe residue was purified by silica gel chromatography (hexane:ethylacetate=2:1) to give the title compound (58.5 mg, 0.123 mmol, 8.7%).

Synthesis Method B (Step B-1) Synthesis of 4-chloromethylbenzaldehyde

Under an argon atmosphere, 4-chloromethylbenzoic acid (15.08 g, 88.40mmol) was dissolved in THF (150 ml), and 1M borane-THF complex (135 ml,135.00 mmol) was slowly added dropwise under ice-cooling. The mixturewas stirred at room temperature for 2 hours, 1N sulfuric acid (160 ml)was added, and the mixture was stirred for 1 hour and extracted withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure, and the obtained crude product was dissolved indichloromethane (300 ml). Manganese dioxide (76.94 g, 885.0 mmol) wasadded, and the mixture was stirred overnight at room temperature. Afterfiltration through celite, the filtrate was concentrated under reducedpressure to give the title compound (11.93 g, 87%).

¹H-NMR (300 MHz, CDCl₃) δ=4.64 (2H, s), 7.57 (2H, d, J=6.9 Hz), 7.89(2H, d, J=6.9 Hz), 10.03 (1H, s).

(Step B-2) Synthesis of 4-chloromethylbenzaldehyde oxime

4-Chloromethylbenzaldehyde (11.93 g, 77.17 mmol) was dissolved inethanol (200 ml), hydroxylamine hydrochloride (10.73 g, 154.41 mmol) wasadded, and the mixture was stirred at 50° C. for 3 hours. Ethanol wasevaporated under reduced pressure, water was added, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure to give the title compound (12.69 g,97%).

¹H-NMR (300 MHz, CDCl₃) δ=4.59 (2H, s), 7.40 (2H, d, J=7.2 Hz), 7.57(2H, d, J=7.2 Hz), 7.85-8.10 (1H, m), 8.14 (H, s).

(Step B-3) Synthesis of N-hydroxy-4-chloromethylbenzenecarboxyimidoylchloride

4-Chloromethylbenzaldehyde oxime (12.69 g, 74.82 mmol) was dissolved inDMF (250 ml), N-chlorosuccinimide (12.00 g, 89.87 mmol), and then 4Nhydrogen chloride in 1,4-dioxane (120 ml) were added, and the mixturewas stirred at room temperature for 30 min. Water was added, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure to give the titlecompound (15.27 g, 100%).

¹H-NMR (300 MHz, CDCl₃) δ=4.60 (2H, s), 7.43 (2H, d, J=7.5 Hz), 7.84(2H, d, J=7.5 Hz), 8.12-8.19 (1H, m).

(Step B-4) Synthesis of methyl3-(4-chloromethylphenyl)isoxazole-4-carboxylate

N-Hydroxy-4-chloromethylbenzenecarboxyimidoyl chloride (15.27 g, 74.82mmol) was dissolved in dichloromethane (300 ml), methyl3-methoxyacrylate (10.43 g, 89.82 mmol) was added, and triethylamine (21ml, 151 mmol) was slowly added dropwise. The mixture was stirredovernight at room temperature. Water was added, and the mixture wasextracted with dichloromethane. The extract was washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure, and the obtained crude product waspurified by silica gel chromatography (hexane:ethyl acetate=5:1) to givethe title compound (9.67 g, 51%).

¹H-NMR (300 MHz, CDCl₃) δ=3.84 (3H, s), 4.63 (2H, s), 7.49 (2H, d, J=6.9Hz), 7.70 (2H, d, J=6.9 Hz), 9.01 (1H, s).

(Step B-5) Synthesis of 3-(4-chloromethylphenyl)isoxazole-4-carboxylicAcid

Methyl 3-(4-chloromethylphenyl)isoxazole-4-carboxylate (7.59 g, 30.16mmol) was dissolved in THF-water (2:1, 225 ml), lithium hydroxidemonohydrate (5.06 g, 120.6 mmol) was added, and the mixture was stirredat room temperature for 6 hours. THF was evaporated under reducedpressure, 2N hydrochloric acid was added to weakly acidify the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure to give thetitle compound (7.14 g, 100%).

¹H-NMR (300 MHz, CDCl₃) δ=4.70 (2H, s), 7.52 (2H, d, J=8.4 Hz), 7.77(2H, d, J=8.4 Hz), 9.31 (1H, s).

(Step B-6) Synthesis of 1-(2-chlorophenyl)ethyl[3-(4-chloromethylphenyl)isoxazolyl]-carbamate

3-(4-Chloromethylphenyl)isoxazole-4-carboxylic acid (5.78 g, 24.32mmol), 1-(2-chlorophenyl)ethanol (7.66 g, 48.91 mmol),diphenylphosphoryl azide (8.11 g, 29.47 mmol), and triethylamine (3.71g, 36.66 mmol) were dissolved in toluene (70 ml), and the mixture wasstirred at 90° C. for 2 hours. The solvent was evaporated under reducedpressure, water was added, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the obtained crude product was purified by silica gelchromatography (hexane:ethyl acetate=4:1) to give the title compound(6.78 g, 71%).

¹H-NMR (300 MHz, CDCl₃) δ=1.57 (3H, d, J=6.6 Hz), 4.62 (2H, s), 6.23(1H, q, J=6.6 Hz), 6.36 (1H, brs), 7.20-7.62 (8H, m), 8.89 (1H, s).

MS (ESI) m/z 391 (M+H)⁺.

(Step B-7) Synthesis of methyl3-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)propionate

1-(2-Chlorophenyl)ethyl [3-(4-chloromethylphenyl)isoxazolyl]carbamate(3.51 g, 8.97 mmol) was dissolved in dichloromethane (70 ml), methyl3-mercaptopropionate (4.46 g, 37.11 mmol) and triethylamine (5.45 g,53.86 mmol) were added, and the mixture was stirred overnight at roomtemperature. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel chromatography (hexane:ethylacetate=4:1) to give the title compound (2.80 g, 66%). The ¹H-NMR and MSspectrum of the compound obtained here matched with the spectrum of thecompound obtained in Example 1, Step A-7.

Example 2 Synthesis of3-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)propionicAcid (Compound 2)

To a solution of methyl3-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)propionate(37 mg, 0.078 mmol) obtained according to Example 1 in tetrahydrofuran(1 ml) was added 1N lithium hydroxide solution (1 ml), and the mixturewas stirred at room temperature for 2 hours. 1N Hydrochloric acid (1.5ml) was added, and the mixture was partitioned by adding ethyl acetate(3 ml). The organic layer was washed with saturated aqueous sodiumchloride solution and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure to give the title compound (35.0mg, 0.076 mmol, 97%).

Example 3 Synthesis of3-(4-{4-[(1R)-1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)propionicAcid (Compound 3)

The title compound was synthesized by a method utilizing opticalresolution of a racemate by chromatography using an optically activecolumn (Synthesis Method A) and a method utilizing the Curtius reactionusing, (1R)-1-(2-chlorophenyl)ethanol

(Synthesis Method B). Synthesis Method A. (Step A-1) Synthesis of methyl3-(4-{4-[(1R)-1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)propionateby Optical Resolution

Methyl3-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)propionate(110 mg, 0.232 mmol) was subjected to optical resolution by highperformance liquid chromatography (HPLC) (hexane:ethanol=8:2) usingCHIRALCEL OD column (2 cm I.D.×25 cm L; DAICEL CHEMICAL IND., LTD) togive the title compound (R form, 54 mg, 49%) along with its S form (55mg, 50%). The optical purity was determined by HPLC analysis using anoptically active column.

R form:

MS (ESI) m/z 475 (M+H)⁺.

optical purity=98% ee (HPLC analysis: CHIRALCEL OD (0.46 cm I.D.×25 cmL), hexane:ethanol=85:15, flow rate=1.0 ml/min, retention time 9.54 min)

S form:

optical purity=90% ee (HPLC analysis: CHIRALCEL OD (0.46 cm I.D.×25 cmL), hexane:ethanol=85:15, flow rate=1.0 ml/min, retention time 10.91min)

(Step A-2) Synthesis of3-(4-{4-[(1R)-1′-(2-chlorophenyl)ethoxycarbonylamino)]-3-isoxazolyl}benzylsulfanyl)propionicAcid

The title compound (58 mg, 0.126 mmol, 100%) was obtained from methyl3-(4-{4-[(1R)-1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)-propionate(42 mg, 0.0885 mmol) according to the method of Example 2.

Synthesis Method B. (Step B-1) Synthesis of(R)-1′-(2-chlorophenyl)ethanol

Reaction was carried out using 2′-chlcroacetophenone (11.90 g, 76.77mmol) and (+)-B-chlorodiisopinocamphenylborane ((+)-DIP-Cl) (25.00 g,77.88 μmmol) and according to J. Org. Chem., 1985, vol. 50, p. 5446; and1988, vol. 53, p. 2916, to give the title compound (8.81 g, 72%). Theoptical purity was determined by HPLC analysis using an optically activecolumn after conversion to the acetate (using acetic anhydride andtriethylamine in dichloromethane).

[α]_(D)=57.8° (CH₂Cl₂, c=1.83)

optical purity=92% ee (HPLC analysis: CHIRALCEL OD (0.46 cm I.D.×25 cmL), hexane:ethanol=99:1, flow rate=1.0 ml/min, retention time R form4.85 min (peak area 96.1%), S form 5.84 min (peak area 3.9%)

(Step B-2) Synthesis of3-(4-{4-[(1R)-1′-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)propionicAcid

Reactions similar to those of Step B-6 and B-7 of Example 1 were carriedout using 3-(4-chloromethylphenyl)isoxazole-4-carboxylic acidsynthesized in Step B-5 of Example 1 and (R)-1-(2-chlorophenyl)ethanol,and hydrolysis was further carried out in the same manner as in Example2 to give the title compound. The ¹H-NMR and MS spectrum of the compoundobtained here matched with the spectrum of the compound obtained in StepA-2 of Example 3.

Example 4 Synthesis ofN-acetyl-S-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzyl)-L-cysteine(Compound 4)

Reaction similar to that of Step B-7 of Example 1 was carried out usingCompound 1 and N-acetyl-L-cysteine to give the title compound.

Example 5 Synthesis of2-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)ethanesulfonicAcid (Compound 5)

Reaction similar to that of Step B-7 of Example 1 was carried out usingCompound 1 (100 mg, 0.256 mmol) and sodium 2-mercaptoethanesulfonate(127 mg, 0.774 mmol) to give the title compound (50 mg, 39%).

Example 6 Synthesis of3-(4-{4-[(1R)-1-(2-bromophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)propionicAcid (Compound 6) (Step 1) Synthesis of (1R)-1-(2-bromophenyl)ethyl[3-(4-chloromethylphenyl)-isoxazolyl]carbamate

Reaction was carried out according to the method of Step B-6 of Example1 using 3-(4-chloromethylphenyl)isoxazole-4-carboxylic acid (compound ofStep B-5 of Example 1) (748 mg, 3.17 mmol) and(R)-1-(2-bromophenyl)ethanol (744 mg, 3.70 mmol) to give the titlecompound (649 mg, 47%).

(Step 2) Synthesis of methyl3-(4-{4-[(1R)-1-(2-bromophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)propionate

Reaction was carried out according to the method of Step B-7 of Example1 using (1R)-1-(2-bromophenyl)ethyl[3-(4-chloromethylphenyl)isoxazolyl]carbamate (287 mg, 8.97 mmol) andmethyl 3-mercaptopropionate (240 mg, 2.00 mmol) to give the titlecompound (284 mg, 83%).

MS (ESI) m/z 519 (M+H)⁺, 521 (M+2+H)⁺.

(Step 3) Synthesis of3-(4-{4-[(1R)-1-(2-bromophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)propionicAcid

Reaction was carried out in the same manner as in Example 2 using methyl3-(4-{4-[(1R)-1-(2-bromophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)-propionate(138 mg, 0.266 mmol) to give the title compound (70 mg, 52%).

Example 7 Synthesis ofN-acetyl-S-(4-{4-[(1R)-1-(2-bromophenyl)-ethoxycarbonylamino]-3-isoxazolyl}benzyl)-L-cysteine(Compound 7)

Reaction was carried out in the same manner as in Step B-7 of Example 1using

(1R)-1-(2-bromophenyl)ethyl[3-(4-chloromethylphenyl)isoxazolyl]carbamate (compound of Step 1 ofExample 6)(102 mg, 0.234 mmol) and N-acetyl-L-cysteine to give the titlecompound (88 mg, 67%).

Example 8 Synthesis of3-(4-{4-[1-(2-chloro-1-cyclopentenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)propionicAcid (Compound 8) (Step 1) Synthesis of2-chloro-1-cyclopentenecarbaldehyde

Under an argon atmosphere, cyclopentanone (500 mg, 5.94 mmol) wasdissolved in anhydrous toluene (10 ml), anhydrous dimethylformamide (687μl, 8.91 mmol) and phosphorus oxychloride (830 μl, 8.91 mmol) were addeddropwise, and the mixture was stirred at room temperature for 2 hours.Water (15 ml) was added, and the mixture was stirred for 30 minutes. 4NAqueous sodium hydroxide solution (9 ml) was added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium chloride solution and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure togive the title compound (636 mg, 4.87 mmol, 82.0%).

(Step 2) Synthesis of 1-(2-chloro-1-cyclopentenyl)ethanol

Under an argon atmosphere, 2-chloro-1-cyclopentenecarbaldehyde (630 mg,4.82 mmol) was dissolved in anhydrous tetrahydrofuran (19 ml),methylmagnesium bromide (1.4M toluene solution, 4.1 ml) was addeddropwise at 0° C., and the mixture was stirred at room temperature for30 minutes. Isopropanol (2 ml) was added at 0° C., and the solvent wasevaporated under reduced pressure. 1N Hydrochloric acid was added, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated aqueous sodium chloride solution and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel chromatography(hexane:ethyl acetate=10:1-6:1) to give the title compound (294 mg, 2.01mmol, 41.6%).

(Step 3) Synthesis of 1-(2-chloro-1-cyclopententyl)ethyl[3-(4-chloromethylphenyl)-4-isoxazolyl]carbamate

The title compound (435 mg, 1.14 mmol, 67.9%) was obtained from3-(4-chloromethylphenyl)isoxazole-4-carboxylic acid (500 mg, 2.10 mmol)and 1-(2-chloro-1-cyclopentenyl)ethanol (243 mg, 1.68 mmol) according tothe method of Step B-6 of Example 1.

MS (ESI) m/z 381 (M+H)⁺.

(Step 4) Synthesis of methyl3-(4-{4-[1-(2-chloro-1-cyclopentenyl)-ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanylpropionate

The title compound (324 mg, 0.697 mmol, 70.4%) was obtained from1-(2-chloro-1-cyclopentenyl)ethyl[3-(4-chloromethyl-phenyl)-4-isoxazolyl]carbamate (375 mg, 0.989 mmol)and methyl 3-mercaptopropioiate (329 μl, 2.97 mmol) according to themethod of Step B-7 of Example 1.

MS (ESI) m/z 465 (M+H)⁺.

(Step 5) Synthesis of3-(4-{4-[1-(2-chloro-1-cyclopentenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)propionicAcid

The title compound (56.3 mg, 0.125 mmol, 58.1%) was obtained from methyl3-(4-{4-[1-(2-chloro-1-cyclopentenyl)ethoxycarbonylamino]-3-isoxazolyl}-benzylsulfanyl)propionate(100 mg, 0.215 mmol) according to the method of Example 2.

Example 9 Synthesis of3-(4-{4-[(1R)-1-(2-chloro-1-cyclopentenyl)ethoxycarbonyl-amino]-3-isoxazolyl}benzylsulfanyl)propionicAcid (Compound 9) (Step 1) Synthesis of methyl3-(4-{4-[(1R)-1-(2-(chloro-1-cyclopentenyl)-ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanylpropionate

Methyl3-(4-{4-[1-(2-chloro-1-cyclopentenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanylpropionate(156 mg, 0.336 mmol) was subjected to optical resolution by highperformance liquid chromatography (HPLC) (hexane:isopropanol=9:1) usinga CHIRALCEL OD column (2 cm I.D.×25 cm L; DAICEL CHEMICAL IND., LTD) togive the title compound (R form, 30 mg, 19%) along with its S form (38mg, 25%). The optical purity was determined by HPLC analysis using anoptically active column.

R form:

MS (ESI) m/z 465 (M+H)⁺.

[α]_(D)=−27.6° (MeOH, c=0.590)

optical purity=95% ee (HPLC:CHIRALCEL OD (0.46 cm I.D.×25 cm L),hexane:isopropanol=9:1, flow rate=1.0 ml/min, retention time 16.34 min)form:

[α]_(D)=25.5° (MeOH, c=0.675)

optical purity=93% ee (HPLC:CHIRALCEL OD (0.46 cm I.D.×25 cm L),

hexane:isopropanol=9:1, flow rate=1.0 ml/min, retention time 18.54 min)

(Step 2) Synthesis of3-(4-{4-[(1R)-1-(2-chloro-1-cyclopentenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)propionicAcid

The title compound (20.5 mg, 0.0455 mmol, 96.7%) was obtained frommethyl3-(4-{4-[(1R)-1-(2-chloro-1-cyclopentenyl)ethoxylcarbonylamino]-3-isoxazolyl}-benzylsulfanylpropionate(21.9 mg, 0.0471 mmol) according to the method of Example 2.

Example 10 Synthesis of3-(4-{4-[1-(2-chloro-1-cyclohexenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)propionicAcid (Compound 10) (Step 1) Synthesis of2-chloro-1-cyclohexenecarbaldehyde

The title compound (1.32 g, 9.13 mmol, 92.3%) was obtained fromcyclohexanone (1.0 g, 10.2 mmol) according to a method similar to thatof Step 1 of Example 8.

(Step 2) Synthesis of 1-(2-chloro-1-cyclohexenyl)ethanol

The title compound (335 mg, 2.09 mmol, 46.3%) was obtained from2-chloro-1-cyclohexenecarbaldehyde (650 mg, 4.50 mmol) according to amethod similar to that of Step 2 of Example 8.

(Step 3) Synthesis of 1-(2-chloro-1-cyclohexenyl)ethyl[3-(4-chloromethylphenyl)-4-isoxazolyl]carbamate

The title compound (521 mg, 1.32 mmol, 78.4%) was obtained from3-(4-chloromethylphenyl)isoxazole-4-carboxylic acid (500 mg, 2.10 mmol)and 1-(2-chloro-1-cyclohexenyl)ethanol (270 mg, 1.68 mmol) according tothe method of Step B-6 of Example 1.

MS (ESI) m/z 396 (M+H)⁺.

(Step 4) Synthesis of methyl3-(4-{4-[1-(2-chloro-1-cyclohexenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)propionate

The title compound (437 mg, 0.913 mmol, 79.6%) was obtained from1-(2-chloro-1-cyclohexenyl)ethyl[3-(4-chloromethylphenyl)-4-isoxazolyl]carbamate (435 mg, 1.15 mmol) andmethyl 3-mercaptopropionate (380 μl, 3.44 mmol) according to the methodof Step B-7 of Example 1.

MS (ESI) m/z 479 (M+H)⁺.

(Step 5) Synthesis of3-(4-{4-[1-(2-chloro-1-cyclohexenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)propionicAcid

The title compound (94.7 mg, 0.204 mmol, 94.9%) was obtained from methyl3-(4-{4-[1-(2-chloro-1-cyclohexenyl)ethoxycarbonylamino]-3-isoxazolyl}benzyl-sulfanylpropionoate(103 mg, 0.215 mmol) according to the method of Example 2.

Example 11 Synthesis of3-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfonyl)propionicAcid (Compound 11) (Step 1) Synthesis of methyl3-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfonyl)propionate

To a solution of methyl3-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)propionate(Compound 1) (82 mg, 0.173 mmol) in dichloromethane (10 ml) was addedm-chloroperbenzoic acid (92 mg, 0.533 mmol), and the mixture was stirredat room temperature for 2 hours. 1N Sodium carbonate aqueous solutionwas added to the reaction mixture, and the mixture was extracted withdichloromethane. The organic layer was washed with saturated brine anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure, and the obtained crude product was purified by silicagel chromatography (hexane:ethyl acetate=4:1) to give the title compound(83 mg, 95%).

MS (ESI) m/z 507 (M+H)⁺.

(Step 2) Synthesis of3-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}-benzylsulfonyl)propionicAcid

Reaction similar to that of Example 2 was carried out using methyl3-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfonyl)propionateto give the title compound (24 mg, 30%).

Example 12 Synthesis of3-(4-{4-[(1R)-1-(2-bromophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfonyl)propionicAcid (Compound 12)

Reaction similar to that of Example 11 was carried out using methyl3-(4-{4-[(1R)-1-(2-bromophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)propionate

(compound of Step 2 of Example 6) to give the title compound (55 mg,76%).

Example 13 Synthesis of3-(4-{4-[1-(2-chloro-1-cyclohexenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfonyl)propionicAcid (Compound 13)

Reaction similar to that of Example 11 was carried out using methyl3-(4-{4-[1-(2-chloro-1-cyclohexenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)propionate(compound of Step 4 Example 10) to give the title compound (6.2 mg,11%).

Example 14 Synthesis of{[2-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)ethyl]thio}aceticAcid (Compound 14) (Step 1) Synthesis of 4-(2-chloroethyl)benzaldehyde

4-(2-Chloroethyl)benzoic acid (2.00 g, 10.83 mmol) was dissolved in THF(40 ml) under an argon atmosphere, and 1M borane-THF complex (16 ml,16.00 mmol) was slowly added dropwise under ice-cooling. After stirringat room temperature for 2 hours, 1N sulfuric acid (36 ml) was added, andthe mixture was stirred for 1 hour and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure, andthe obtained crude product was dissolved in dichloromethane (50 ml).Manganese dioxide (10.00 g) was added, and the mixture was stirredovernight at room temperature. After filtration through celite, thefiltrate was concentrated under reduced pressure to give the titlecompound (1.71 g, 91%).

(Step 2) Synthesis of 4-(2-chloroethyl)benzaldehyde oxime

4-(2-Chloroethyl)benzaldehyde (1.70 g, 10.08 mmol) was dissolved inethanol (35 ml), hydroxylamine hydrochloride (1.05 g, 1:5.11 mmol) wasadded, and the mixture was stirred at 50° C. for 2 hours. Ethanol wasevaporated under reduced pressure, and water was added. The mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure to give the title compound (1.75 g,95%).

(Step 3) Synthesis of N-hydroxy-4-(2-chloroethyl))benzenecarboxyimidoylchloride

4-(2-Chloroethyl)benzaldehyde oxime (1.74 g, 9.48 mmol) was dissolved inDMF (40 ml), N-chlorosuccinimide (1.52 g, 11.38 mmol), and then 4Nhydrogen chloride in 1,4-dioxane (20 ml) were added, and the mixture wasstirred at room temperature for 1 hour. Water was added, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine:and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure to give the title compound(2.07 g, 100%).

(Step 4) Synthesis of methyl3-(4-(2-chloroethyl)phenyl)isoxazole-4-carboxylate

N-Hydroxy-4-(2-chloroethyl)benzenecarboxyimidoyl chloride (2.07 g, 9.48mmol) was dissolved in dichloromethane (5 ml), methyl 3-methoxyacrylate(1.32 g, 11.37 mmol) was added, and triethylamine (1.92 g, 18.97 mmol)was slowly added dropwise. The mixture was stirred overnight at roomtemperature. Water was added, and the mixture was extracted withdichloromethane. The extract was washed with saturated brine and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the obtained crude product was purified by silica gelchromatography (hexane:ethyl acetate=5:1) to give the title compound(1.46 g, 58%). MS (ESI) m/z 266 (M+H)⁺.

(Step 5) Synthesis of 3-(4-(2-chloroethyl)phenyl)isoxazole-4-carboxylicAcid

Methyl 3-(4-(2-chloroethyl)phenyl)isoxazole-4-carboxylate (1.46 g, 5.49mmol) was dissolved in THF-water (2:1, 30 ml), lithium hydroxidemonohydrate (922 mg, 21.97 mmol) was added, and the mixture was stirredat room temperature for 6 hours. THF was evaporated under reducedpressure, 2N hydrochloric acid was added to weak-acidify the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure to give thetitle compound (1.38 g, 100%).

MS (ESI) m/z 252 (M+H)⁺.

(Step 6) Synthesis of 1-(2-chlorophenyl)ethyl[3-(4-(2-chloroethyl)phenyl)isoxazolyl]-carbamate

3-(4-(2-Chloroethyl)phenyl)isoxazole-4-carboxylic acid (710 mg, 2.82mmol), 1-(2-chlorophenyl)ethanol (530 mg, 3.38 mmol), diphenylphosphorylazide (930 mg, 3.38 mmol), and triethylamine (1.43 g, 14.13 mmol) weredissolved in toluene (15 ml), and the mixture was stirred at 90° C. for1 hour. The solvent was evaporated under reduced pressure, and water wasadded. The mixture was extracted with ethyl acetate. The organic layerwas washed with saturated brine and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure, and the obtainedcrude product was purified by silica gel chromatography (hexane:ethylacetate=5:1) to give the title compound (963 mg, 84%).

MS (ESI) m/z 405 (M+H)⁺.

(Step 7) Synthesis of methyl{[2-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)ethyl]thio}acetate

1-(2-Chlorophenyl)ethyl [3-(4-(2-chloroethyl)phenyl)isoxazolyl]carbamate(481 mg, 1.19 mmol) was dissolved in chloroform (10 ml), methylthioglycolate (379 mg, 3.57 mmol), and triethylamine (600 mg, 5.93 mmol)were added, and the mixture was stirred overnight at 50° C. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel chromatography (hexane:ethyl acetate=4:1) to give the titlecompound (190 mg, 34%).

MS (ESI) m/z 475 (M+H)⁺.

(Step 8) Synthesis of{[2-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)ethyl]thio}aceticAcid

Reaction similar to that of Example 2 was carried out using methyl{[2-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)ethyl]thio}acetate(183 mg, 0.385 mmol) to give the title compound (123 mg, 69%).

Example 15 Synthesis of{3-[2-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)ethyl]thio}propionicAcid (Compound 15) (Step 1) Synthesis of methyl{3-[2-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)ethyl]thio}propionate

Reaction similar to that of Step 7 of Example 14 was carried out using1-(2-chlorophenyl)ethyl [3-(4-(2-chloroethyl)phenyl)isoxazolyl]carbamate(481 mg, 1.19 mmol) obtained in Step 6 of Example 14 and methyl3-mercaptopropionate (430 mg, 3.58 mmol) to give the title compound (44mg, 8%).

MS (ESI) m/z 489 (M+H)⁺.

(Step 2) Synthesis of{3-[2-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)ethyl]thio}propionicAcid

Reaction similar to that of Example 2 was carried out using methyl{3-[2-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)ethyl]thio}propionate(44 mg, 0.090 mmol) to give the title compound (29 mg, 68%).

Example 16 Synthesis of{[2-(4-{4-[1-(2-chlorocyclopentenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)ethyl]thio}aceticAcid (Compound 16) (Step 1) Synthesis of 1-(2-chlorocyclopentenyl)ethyl{3-[4-(2-chloroethyl)phenyl]isoxazolyl}carbamate

Reaction similar to that of Step B-6 of Example 1 was carried out using3-(4-(2-chloroethyl)phenyl)isoxazole-4-carboxylic acid (308 mg, 1.22mmol) and 1-(2-chlorocyclopentenyl)ethanol (270 mg, 1.84 mmol) to givethe title compound (482 mg, 100%).

MS (ESI) m/z 395 (M+H)⁺

(Step 2) Synthesis of methyl{[2-(4-{4-[1-(2-chlorocyclopentenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)ethyl]thio}acetate

Reaction similar to that of Step 7 of Example 14 was carried out using1-(2-chlorocyclopentenyl)ethyl{3-[4-(2-chloroethyl)phenyl]isoxazolyl}carbamate (482 mg, 1.22 mmol) togive the title compound (69 mg, 12%).

MS (ESI) m/z 465 (M+H)⁺.

(Step 3) Synthesis of{[2-(4-{4-[1-(2-chlorocyclopentenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)ethyl]thio}aceticAcid

Reaction similar to that of Example 2 was carried out using methyl{[2-(4-{4-[1-(2-chlorocyclopentenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)ethyl]thio}acetate(69 mg, 0.148 mmol) to give the title compound (36 mg, 54%).

Example 17 Synthesis of{[2-(4-{4-[1-(2-chlorocyclohexenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)ethyl]thio}aceticAcid (Compound 17) (Step 1) Synthesis of 1-(2-chlorocyclohexenyl)ethyl[3-(4-(2-chloroethyl)phenyl)-isoxazolyl]carbamate

Reaction similar to that of Step B-6 of Example 1 was carried out using3-(4-(2-chloroethyl)phenyl)isoxazole-4-carboxylic acid (262 mg, 1.04mmol) and 1-(2-chlorocyclohexenyl)ethanol (256 mg, 1.59 mmol) to givethe title compound (396 mg, 93%).

MS (ESI) m/z 409 (M+H)⁺.

(Step 2) Synthesis of methyl{[2-(4-{4-[1-(2-chlorocyclohexenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)ethyl]thio}acetate

Reaction similar to that of Step 7 of Example 14 was carried out using1-(2-chlorocyclohexenyl)ethyl[3-(4-(2-chloroethyl)phenyl)isoxazolyl]carbamate (396 mg, 0.97 mmol) togive the title compound (108 mg, 23%).

MS (ESI) m/z 479 (M+H)⁺.

(Step 3) Synthesis of{[2-(4-{4-[1-(2-chlorocyclohexenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)ethyl]thio}aceticAcid

Reaction similar to that of Example 2 was carried out using methyl{[2-(4-{4-[1-(2-chlorocyclohexenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)ethyl]thio}acetate(100 mg, 0.209 mmol) to give the title compound (79 mg, 81%).

Example 18 Synthesis of3-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-5-isoxazolyl}benzylsulfanyl)propionicAcid (Compound 18) (Step 1) Synthesis of tert-butyl3-(tert-butyldimethylsilyl)oxy-3-(4-chloromethylphenyl)propionate

Under an argon atmosphere, to a suspension (50 ml) of Bu₂Sn(OTf)₂ (690mg, 1.30 mmol) in dichloromethane was added dropwise a solution (10 ml)of 4-chloromethylbenzaldehyde (2.00 g, 12.94 mmol) in dichloromethane at−78° C., then a solution (10 ml) of1-tert-butoxy-1-[(tert-butyldimethylsilyl)oxy]ethene (6.10 g, 26.47mmol) in dichloromethane was added dropwise, and the mixture was stirredfor 2 hours. Water was added, and the mixture was extracted withdichloromethane. The extract was washed with saturated brine and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the obtained crude product was purified by silica gelchromatography (hexane:ethyl acetate=19:1) to give the title compound(4.96 g, 100%).

(Step 2) Synthesis of tert-butyl3-hydroxy-3-(4-{[(3-methoxy-3-oxopropyl)thio]-methyl}phenyl)propionate

To a solution (40 ml) of tert-butyl3-(tert-butyldimethylsilyl)oxy-3-(4-chloromethylphenyl)propionate (3.25g, 8.44 mmol) in chloroform were added methyl 3-mercaptopropionate (1.12g, 9.32 mmol), triethylamine (2.4 ml, 17.29 mmol), andtetrabutylammonium iodide (156 mg, 0.42 mmol), and the mixture wasstirred overnight at 50° C. The solvent was evaporated under reducedpressure and water was added. The mixture was extracted with ethylacetate, and the extract was washed with saturated brine and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure again. The obtained crude product was dissolved in THF (35 ml),1M tetrabutylammonium fluoride-THF solution (8.5 ml, 8.50 mmol) wasadded, and the mixture was stirred at room temperature for 4 hours. Thesolvent was evaporated under reduced pressure, water was added, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure, and the obtained crudeproduct was purified by silica gel chromatography (hexane:ethylacetate=3:1) to give the title compound (711 mg, 24%).

(Step 3) Synthesis of tert-butyl3-(4-{[(3-methoxy-3-oxopropyl)thio]methyl}phenyl)-3-oxopropionate

To a solution (15 ml) of tert-butyl3-hydroxy-3-(4-{[(3-methoxy-3-oxopropyl)thio]methyl}phenyl)propionate(695 mg, 1.96 mmol) in dichloromethane were added sodium acetate (810mg, 9.87 mmol) and pyridinium dichromate (885 mg, 2.35 mmol), and themixture was stirred overnight at room temperature. Ethyl ether was addedto the reaction mixture, and the mixture was filtered. The filtrate wasconcentrated under reduced pressure, and the obtained crude product waspurified by silica gel chromatography (hexane:ethyl acetate=5:1) to givethe title compound (494 mg, 71%).

(Step 4) Synthesis of tert-butyl5-(4-{[(3-methoxy-3-oxopropyl)thio]methyl}-phenyl)isoxazole-4-carboxylate

To tert-butyl3-(4-{[(3-methoxy-3-oxopropyl)thio]methyl}phenyl)-3-oxopropionate (472mg, 1.34 mmol) was added N,N-dimethylformamide dimethylacetal (5 ml),and the mixture was stirred at 100° C. for 1 hour. The solvent wasevaporated under reduced pressure, and the residue was dissolved inethanol (10 ml). Hydroxylamine hydrochloride (280 mg, 4.03 mmol) wasadded, and the mixture was stirred at 70° C. for 2 hours. The solventwas evaporated under reduced pressure and water was added. The mixturewas extracted with ethyl acetate, and the extract was washed withsaturated brine and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure, and the obtained crude product waspurified by silica gel chromatography (hexane:ethyl acetate=5:1) to givethe title compound (330 mg, 65%).

(Step 5) Synthesis of5-(4-{[(3-methoxy-3-oxopropyl)thio]methyl}phenyl)isoxazole-4-carboxylicAcid

To tert-butyl5-(4-{[(3-methoxy-3-oxopropyl)thio]methyl}phenyl)isoxazole-4-carboxylate(300 mg, 0.80 mmol) was added 4N hydrogen chloride in 1,4-dioxane (10ml), and the mixture was stirred overnight at 100° C. The solvent wasevaporated under reduced pressure to give the title compound (250 mg,98%).

(Step 6) Synthesis of methyl3-(4-[4-[1-(2-chlorophenyl)ethoxycarbonylamino]-5-isoxazolyl]benzylsulfanyl)propionate

Reaction similar to that of Step B-6 of Example 1 was carried out using5-(4-{[(3-methoxy-3-oxopropyl)thio]methyl}phenyl)isoxazole-4-carboxylicacid (81 mg, 0.25 mmol) and 1-(2-chlorophenyl)ethanol (57 mg, 0.36 mmol)to give the title compound (24 mg, 20%).

MS (ESI) m/z 475 (M+H)⁺.

(Step 7) Synthesis of3-(4-[4-[1-(2-chlorophenyl)ethoxycarbonylamino]-5-isoxazolyl]-benzylsulfanyl)propionicAcid

To a solution (1 ml) of methyl3-(4-[4-[1-(2-chlorophenyl)ethoxy-carbonylamino]-5-isoxazolyl]benzylsulfanyl)propionate(22 mg, 0.046 mmol) in ethanol was added 2N hydrochloric acid (2 ml),and the mixture was stirred at 50° C. for 4 hours. The solvent wasevaporated under reduced pressure, and water was added. The mixture wasextracted with ethyl acetate, and the extract was dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure, andthe obtained crude product was purified by silica gel chromatography(dichloromethane:methanol=9:1) to give the title compound (10 mg, 47%).

Example 19 Synthesis of5-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)-4-pentanoicAcid (Compound 19) (Step 1) Synthesis of 4-iodobenzaldehyde oxime

The title compound (1.58 g, 6.40 mmol, 96.3%) was obtained from4-iodobenzaldehyde (1.54 g, 6.63 mmol) according to a method similar tothat of Step B-2 of Example 1.

MS (ESI) m/z 248 (M+H)⁺.

(Step 2) Synthesis of N-hydroxy-4-iodobenzenecarboxyimidoyl chloride

The title compound (1.79 g, 6.36 mmol, 100%) was obtained from4-iodobenzaldehyde oxime (1.57 g, 6.36 mmol) according to a methodsimilar to that of Step B-3 of Example 1.

MS (ESI) m/z 282 (M+H)⁺.

(Step 3) Synthesis of methyl 3-(4-iodophenyl)isoxazole-4-carboxylate

The title compound (1.14 g, 3.47 mmol., 54.7%) was obtained fromN-hydroxy-4-iodobenzenecarboxyimidoyl chloride (1.79 g, 15.36 mmol)according to a method similar to that of Step B-4 of Example 1.

MS (ESI) m/z 330 (M+H)⁺.

(Step 4) Synthesis of 3-(4-iodophenyl)isoxazole-4-carboxylic Acid

The title compound (1.22 g, 3.87 mmol, 100%) was obtained from methyl3-(4-iodophenyl)isoxazole-4-carboxylate (1.14 g, 3.47 mmol) according toa method similar to that of Step B-5 of Example 1.

MS (ESI) m/z 316 (M+H)⁺.

(Step 5) Synthesis of 1-(2-chlorophenyl)ethyl[3-(4-iodophenyl)-4-isoxazolyl]carbamate

The title compound (394 mg, 0.841 mmol, 87.9%) was obtained from3-(4-iodophenyl)isoxazole-4-carboxylic acid (430 mg, 1.37 mmol) and2-chloro-α-methyl-benzylalcohol (127 μl, 0.956 mmol) according to themethod of Step B-6 of Example 1. MS (ESI) m/z 469 (M+H)⁺.

(Step 6) Synthesis of methyl5-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)-4-pentenoate

1-(2-Chlorophenyl)ethyl [3-(4-iodophenyl)-4-isoxazolyl]carbamate (250mg, 0.534 mmol) was dissolved in a mixed solvent ofdiethylisopropylamine (2.5 ml) and 1,4-dioxane (12.5 ml), ethyl4-pentenate (96 mg, 0.748 mmol), tri-o-tolyl-phosphine (65 mg, 0.214mmol), and palladium acetate (12 mg, 0.0534 mmol) were added. Themixture was stirred at 100° C. for 4 hours. 1N Hydrochloric acid wasadded, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated aqueous sodium chloride solution anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure to give the title compound (159 mg, 0.340 mmol, 63.6%).

MS (ESI) m/z 469 (M+H)⁺.

(Step 7) Synthesis of methyl5-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)-4-pentanoate

Methyl5-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}-phenyl)-4-pentenoate(160 mg, 0.299 mmol) was dissolved in ethyl acetate (10 ml), andpalladium carbon (dry, 25 mg) was added. The mixture was hydrogenated atroom temperature for 1 hour. After filtration through celite, thesolvent was evaporated under reduced pressure to give the title compound(14i; mg, 0.315 mmol, 92.2%).

MS (ESI) m/z 471 (M+H)⁺.

(Step 8) Synthesis of5-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)-4-pentanoicAcid

The title compound (63.3 mg, 0.143 mmol, 73.3%) was obtained from methyl5-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)-4-pentanoate(92 mg, 0.195 mmol) according to the method of Example 2.

Example 20 Synthesis of3-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzyloxycarbonylamino)propionicAcid (Compound 20) (Step 1) Synthesis of methyl3-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzyloxycarbonylamino)propionate

1-(2-Chlorophenyl)ethyl [3-(4-chloromethylphenyl)-4-isoxazolyl]carbamate(1.0 g, 2.56 mmol) obtained in Step B-6 of Example 1 was dissolved inN,N-dimethylformamide (30 ml), methyl 3-aminopropionate hydrochloride(1.07 g, 7.67 mmol) and potassium carbonate (2.12 g, 15.3 mmol) wereadded, and the mixture was stirred overnight at 50° C. 1N Hydrochloricacid was added at 0° C. to weak-acidify the reaction system, and themixture was extracted 3 times with ethyl acetate. The organic layer waswashed with saturated aqueous sodium hydrogencarbonate solution andsaturated aqueous sodium chloride solution, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure, andthe residue was purified by column chromatography(methanol:dichloromethane=1:20) to give the title compound (138 mg,11%).

MS (ESI) m/z 502 (M+H)⁺.

(Step 2) Synthesis of3-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzyloxycarbonylamino)propionicAcid

The title compound (94.6 mg, quant.) was obtained from methyl3-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzyloxycarbonylamino)propionate(97.5 mg, 0.194 mmol) according to a method similar to that of Example2.

Example 21 Synthesis of4-[(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)amino]-(2R)-2-hydroxy-4-oxobutanoicAcid (Compound 21)

(2R)-2-Acetoxy-4-[(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)amino]-4-oxobutanoicacid (132 mg, 0.256 mmol) was dissolved in methanol (2.5 ml), 1N aqueoussodium hydroxide solution (2.5 ml) was added, and the mixture wasstirred at room temperature for 1 hour. 1N Hydrochloric acid (2.6 ml)was added at 0° C. to weak-acidify the reaction system, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium chloride solution and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure togive the title compound (111 mg, 92%).

Example 22 Synthesis of4-[4-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-isoxazolyl]phenylacetate (Compound 22) (Step 1) Synthesis of4-(tert-butyldimethylsilyloxy)benzaldehyde oxime

Reaction similar to that of Step B-2 of Example 1 was carried out using4-(tert-butyldimethylsilyloxy)benzaldehyde to give the title compound.

(Step 2) Synthesis of4-(tert-butyldimethylsilyloxy)-N-hydroxybenzenecarboxyimidoyl chloride

Reaction similar to that of Step B-3 of Example 1 was carried out using4-(tert-butyldimethylsilyloxy)benzaldehyde oxime to give the titlecompound.

(Step 3) Synthesis of methyl3-(4-[tert-butyldimethylsilyloxy]phenyl)isoxazole-4-carboxylate

Reaction similar to that of Step B-4 of Example 1 was carried out using4-(tert-butyldimethylsilyloxy)-N-hydroxybenzenecarboxyimidoyl chlorideto give the title compound.

(Step 4) Synthesis of 3-(4-hydroxyphenyl)isoxazole-4-carboxylic acid

Reaction similar to that of Step B-5 of Example 1 was carried out usingmethyl 3-(4-[tert-butyldimethylsilyloxy]phenyl)isoxazole-4-carboxylateto give the title compound.

(Step 5) Synthesis of 3-(4-acetoxyphenyl)isoxazole-4-carboxylic acid

To a solution (120 ml) of 3-(4-hydroxyphenyl)isoxazole-4-carboxylic acid(1.39 g, 6.77 mmol) in dichloromethane were added acetic anhydride (2.07g, 20.28 mmol), triethylamine (3.43 g, 33.90 mmol), and4-N,N-dimethylaminopyridine (84 mg, 0.676 mmol), and the mixture wasstirred at room temperature for 1 hour. The reaction mixture wasconcentrated under reduced pressure and water was added. The mixture wasextracted with ethyl acetate, washed with saturated brine, and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the obtained crude product was purified by silica gelcolumn chromatography (ethyl acetate) to give the title compound (1.50g, 78%).

(Step 6) Synthesis of4-[4-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-isoxazolyl]phenylacetate

Reaction similar to that of Step B-6 of Example 1 was carried out using3-(4-acetoxyphenyl)isoxazole-4-carboxylic acid to give the titlecompound.

Example 23 Synthesis of 1-(2-chlorophenyl)ethyl3-(4-hydroxyphenyl)-4-isoxazolylcarbamate (Compound 23)

To a solution (20 ml) of4-[4-{[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-isoxazolyl]phenylacetate (2.11 g, 5.26 mmol) in tetrahydrofuran was added 1M aqueoussodium hydroxide solution (7.0 ml), and the mixture was stirred at roomtemperature for 7 hours. The reaction mixture was concentrated underreduced pressure, and water was added. The mixture was neutralized with1M hydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with saturated brine and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure to give the titlecompound (1.82 g, 96%).

Example 24 Synthesis of5-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenoxy)pentanoicAcid (Compound 24) (Step 1) Synthesis of ethyl5-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenoxy)pentanoate

To a solution (2 ml) of 1-(2-chlorophenyl)ethyl3-(4-hydroxyphenyl)-4-isoxazolylcarbamate (80 mg, 0.223 mmol) inN,N-dimethylformamide were added potassium carbonate (60 mg, 0.435 mmol)and ethyl 5-bromovalerate (60 mg, 0.287 mmol), and the mixture wasstirred at 100° C. for 1 hour. Water was added, the mixture wasextracted with ethyl acetate, and the extract was washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure, and the obtained residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=4:1) to givethe title compound (59 mg, 55%).

(Step 2) Synthesis of5-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenoxy)pentanoicAcid

The title compound (31 mg, 57%) was obtained from ethyl5-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenoxy)pentanoate(58 mg, 0.12 mmol) according to a method similar to that of Example 2.

Example 25 Synthesis of4-[(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)amino]-4-oxobutanoicAcid (Compound 25) (Step 1) Synthesis of 4-nitrobenzaldehyde oxime

Reaction similar to that of Step B-2 of Example 1 was carried out using4-nitrobenzaldehyde to give the title compound.

(Step 2) Synthesis of N-hydroxy-4-nitrobenzenecarboxyimidoyl chloride

Reaction similar to that of Step B-3 of Example 1 was carried out using4-nitrobenzaldehyde oxime to give the title compound.

(Step 3) Synthesis of methyl 3-(4-nitrophenyl)isoxazole-4-carboxylate

Reaction similar to that of Step B-4 of Example 1 was carried out usingN-hydroxy-4-nitrobenzenecarboxyimidoyl chloride to give the titlecompound.

(Step 4) Synthesis of 3-(4-nitrophenyl)isoxazole-4-carboxylic Acid

Reaction similar to that of Step B-5 of Example 1 was carried out usingmethyl 3-(4-nitrophenyl)isoxazole-4-carboxylate to give the titlecompound.

(Step 5) Synthesis of 1-(2-chlorophenyl)ethyl[3-(4-nitrophenyl)-4-isoxazolyl]carbamate

Reaction similar to that of Step B-6 of Example 1 was carried out using3-(4-nitrophenyl)isoxazole-4-carboxylic acid to give the title compound.

(Step 6) Synthesis of 1-(2-chlorophenyl)ethyl[3-(4-aminophenyl)-4-isoxazolyl]carbamate

To a solution of 1-(2-chlorophenyl)ethyl[3-(4-nitrophenyl)-4-isoxazolyl]-carbamate in ethanol was added 5% Pd—C,and hydrogenation reaction was carried out at room temperature for 1hour. The reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure and purified by silica gel columnchromatography (hexane:ethyl acetate=3:1) to give the title compound.

(Step 7) Synthesis of4-[(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)amino]-4-oxobutanoicAcid

1-(2-Chlorophenyl)ethyl [3-(4-aminophenyl)-4-isoxazolyl]carbamate andsuccinic anhydride were dissolved in acetone, and the mixture wasstirred overnight at room temperature. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified byreversed phase HPLC to give the title compound.

Example 26 Synthesis of(2R)-2-acetoxy-4-[(4-{4-[1-(2-chlorophenyl)ethoxy-carbonylamino]-3-isoxazolyl}phenyl)amino]-4-oxobutanoicAcid (Compound 26)

The title compound (188 mg, 87%) was obtained from1-(2-chlorophenyl)ethyl [3-(4-aminophenyl)-4-isoxazolyl]carbamate (150mg, 0.42 mmol) obtained in Step 6 of Example 25 and(S)-(−)-O-2-acetoxysuccinic anhydride (133 mg, 0.84 mmol) according to amethod similar to that of Step 7 of Example 25.

Example 27 Synthesis of{[2-(4-{4-[(1R)-1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)ethyl]thio}aceticAcid (Compound 27)

Reaction similar to that of Example 14 was carried out using(1R)-1-(2-chlorophenyl)ethanol to give the title compound.

Example 28 Synthesis of3-(4-{4-[(1R)-1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfonyl)propionicAcid (Compound 28)

Reaction similar to that of Example 11 was carried out using(1R)-1-(2-chlorophenyl)ethanol to give the title compound

Example 29 Synthesis of{3-[2-(4-{4-[(1R)-1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)ethyl]thio}propionicAcid (Compound 29)

Reaction similar to that of Example 15 was carried out using(1R)-1-(2-chlorophenyl)ethanol to give the title compound.

Example 30 Synthesis of5-(4-{4-[(1R)-1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)-4-pentenoicAcid (Compound 30)

According to methods similar to those of Step 5 and Step 6 of Example 19using 3-(4-iodophenyl)isoxazole-4-carboxylic acid and(R)-2-chloro-a-methylbenzyl alcohol, methyl5-(4-{4-[(1R)-1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)-4-pentenoatewas synthesized, which was reacted in the same manner as in Example 2 togive the title compound.

Example 31 Synthesis of5-(4-{4-[(1R)-1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)-4-pentanoicAcid (Compound 31)

Reactions similar to those of Step 7 and Step 8 of Example 19 werecarried out using methyl5-(4-{4-[(1R)-1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)-4-pentenoateobtained in Example 30 to give the title compound.

Example 32 Synthesis of6-(4-{4-[(1R)-1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)hexanoicAcid (Compound 32) (Step 1) Synthesis of3-[4-(5-methoxycarbonyl-1-pentenyl)phenyl]isoxazole-4-carboxylic acid

3-(4-Iodophenyl)isoxazole-4-carboxylic acid (315 mg, 1.0 mmol) wasdissolved in a mixed solvent of 1,4-dioxane (5 ml) anddiethylisopropylamine (2.5 ml), methyl 5-hexenoate (179 mg, 1.4 mmol),tri-(o-tolyl)phosphine (122 mg, 0.4 mmol) and palladium acetate (22.4mg, 0.1 mmol) were added, and the mixture was stirred overnight at 100°C.

1N Hydrochloric acid was added, and the mixture was extracted once withethyl acetate. The organic layer was washed with saturated aqueoussodium chloride solution and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel chromatography (hexane:ethyl acetate=7:3-6:4) togive the title compound (250 mg, 79%).

MS (ESI) m/z 316 (M+H)⁺.

(Step 2) Synthesis of methyl6-(4-{4-[(1R)-1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)-5-hexenoate

The title compound (99 mg, 27%) was obtained from3-[4-(5-methoxycarbonyl-1-pentenyl)phenyl]isoxazole-4-carboxylic acid(250 mg, 0.79 mmol) and (1R)-1-(2-chlorophenyl)ethanol (149 mg, 0.95mmol) according to methods similar to those of Step 5 and Step 6 ofExample 19.

MS (ESI) m/z 469 (M+H)⁺.

(Step 3) Synthesis of6-(4-{4-[(1R)-1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)hexanoicAcid

Reactions similar to those of Step 7 and Step 8 of Example 19 werecarried out using methyl6-(4-{4-[(1R)-1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}-phenyl)-5-hexenoateto give the title compound.

Example 33 Synthesis of5-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)-3,3-dimethylpentanoicAcid (Compound 33)

Reactions similar to those of Step 6 to 8 of Example 19 were carried outusing 1-(2-chlorophenyl)ethyl [3-(4-iodophenyl)-4-isoxazolyl]carbamateand methyl 3,3-dimethyl-4-pentenoate to give the title compound.

Example 34 Synthesis of5-(4-{4-[(1R)-1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)-2-methylpentanoicAcid (Compound 34)

Reactions similar to those of Step 6 to 8 of Example 19 were carried outusing 1-(2-chlorophenyl)ethyl [3-(4-iodophenyl)-4-isoxazolyl]carbamateand ethyl 2-methyl-4-pentenoate to give the title compound.

The structural formulas and physicochemical data of the compounds ofExample 1 to 34 are shown in Table 4 to 10. In the Tables, the followingabbreviations are used. Ex: Example No., Dat: physicochemical data.

Experimental Example 1 (1) Establishment of Myofibroblast Like CellStrain Derived from Rat Hepatic Stellate Cell Fraction

A stellate cell fraction was obtained from the liver of male Wistar rataccording to a conventional method (European J. Biochem., 1993, vol.213, p. 815). After subculture for several generations, the cell wascloned by limiting dilution. Well grown 24 clones that formed colonieswere isolated. These clones were stained with αSMA antibody andconfirmed to be all positive and to have Myofibroblast like properties.The Ca²⁺ increase, cell growth, and the like, stimulated by LPA wereexamined in these clones and one kind of clone superior in thereactivity with LPA was selected and used for the measurement ofactivity in the following Examples.

(2) Measurement of Cell Activation (Intracellular Ca²⁺ ConcentrationIncreasing Action)-Inhibitory Activity

The above-mentioned cells were cultured overnight in a 384 well plate at24,000 cells/well and the medium was removed. An assay buffer (0.1% BSA,20 mM HEPES, 1×HBSS, 2.5 mM Probenecid) containing 4 μM of Fluo-3, AM(Biotium) was added, and the cells were stained at 37° C. for 1 hour.Following the buffer containing the dye reagent was removed, and anassay buffer was added, intracellular Ca²⁺ concentration was measuredwith FLIPR (Molecular Devices). Adding a test substance and LPA at thefinal concentration of 5 M, the inhibitory action of the test substanceon the increase in the intracellular Ca²⁺ concentration by LPA wasexamined. The increase in the intracellular Ca²⁺ concentration by LPAaddition without test substance was taken as 100%, that without theaddition of LPA was taken as 0%, and the substrate's concentration(IC₅₀) at inhibiting increase in the intracellular Ca²⁺ concentration by50% was determined.

The results are summarized in Table 11.

TABLE 1 No. R1 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

TABLE 2 No. R1 34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

TABLE 3 No. R3 1 1-(2-fluorophenyl)ethyl 2 1-(2-bromophenyl)ethyl 31-(2-chlorophenyl)ethyl 4 2,2,2-trifluoro-1-phenylethyl 51-(2-chloro-1-cyclopentenyl)ethyl 6 1-(2-chloro-1-cyclohexenyl)ethyl 71-(4-chloro-3-thienyl)ethyl

TABLE 4 Ex Structure Dat 1

¹H-NMR (300 MHz, CDCl₃) δ = 1.58 (3H, d, J = 6.3 Hz), 2.59 (2H, t, J =6.9 Hz), 2.74 (2H, t, J = 6.9 Hz), 3.69 (3H, s), 3.80 (2H, s), 6.25 (1H,q, J = 6.6 Hz), 6.35-6.45 (1H, m), 7.15-7.60 (8H, m), 8.85-8.95 (1H, m).MS (ESI) m/z 475 (M + H)⁺. 2

¹H-NMR (300 MHz, CDCl₃) δ = 1.58 (3H, d, J = 6.6 Hz), 2.55-2.78 (6H, m),3.81 (2H, s), 6.24 (1H, q, J = 6.6 Hz), 6.37-6.45 (1H, m), 7.20-7.60(8H, m), 8.85-8.95 (1H, m). MS (ESI) m/z 461 (M + H)⁺. 3

¹H-NMR (300 MHz, CDCl₃) δ = 1.58 (3H, d, J = 6.6 Hz), 2.55-2.78 (4H, m),3.80 (2H, s), 6.24 (1H, q, J = 6.6 Hz), 6.37-6.45 (1H, m), 7.20-7.60(8H, m), 8.85-8.95 (1H, m). MS (ESI) m/z 461 (M + H)⁺. [α]_(D) = −39.5°(MeOH, c = 0.585) 4

¹H-NMR (300 MHz, CD₃OD) δ = 1.53 (3H, d, J = 5.4 Hz), 2.00 (3H, s), 2.81(1H, dd, J = 13.8, 7.2 Hz), 3.00 (1H, dd, J = 13.8, 4.5 Hz), 3.83 (2H,s), 4.43-4.50 (1H, m), 6.12-6.20 (1H, m), 7.22-7.65 (8H, m), 8.84 (1H,s). MS (ESI) m/z 518 (M + H)⁺. 5

¹H-NMR (300 MHz, CD₃OD) δ = 1.53 (3H, d, J = 6.3 Hz), 2.76-2.86 (2H, m),2.98-3.06 (2H, m), 3.82 (2H, s), 6.15 (1H, q, J = 6.3 Hz), 7.22-7.70(8H, m), 8.84 (1H, s). MS (ESI) m/z 497 (M + H)⁺.

TABLE 5 Ex Structure Dat 6

¹H-NMR(300 MHz, CDCl₃) δ = 1.57(3H, d, J = 6.6 Hz), 2.59-2.66 (2H, m),2.70-2.77(2H, m), 3.80(2H, s), 6.19(1H, q, J = 6.6 Hz), 6.45(1H, brs),7.14-7.59(8H, m), 8.91(1H, s). MS (ESI) m/z 505(M + H)⁺., 507 (M + 2 +H)⁺. 7

¹H-NMR(300 MHz, CDCl₃) δ = 1.56(3H, d, J = 6.6 Hz), 2.05(3H, s),2.82-3.08(2H, m), 3.80(2H, s), 4.42-4.52(1H, m), 6.17(1H, q, J = 6.6Hz), 6.57(1H, brs), 7.12-7.60(8H, m), 8.91(1H, s). MS (ESI) m/z 562 (M +H)⁺., 564 (M + 2 + H)⁺. 8

¹H-NMR (300 MHz, CDCl₃) δ = 1.37(3H, d, J = 6.6 Hz), 1.94(2H, qui, J =7.5 Hz), 2.30-2.78 (8H, m), 3.80(2H, s), 5.77(1H, q, J = 6.6 Hz),6.25-6.37(1H, m), 7.45-7.60(4H, m), 8.90-8.98(1H, m). MS (ESI) m/z 451(M + H)⁺. 9

¹H-NMR(300 MHz, CDCl₃) δ = 1.37(3H, d, J = 6.6 Hz), 1.94(2H, qui, J =7.5 Hz), 2.30-2.78 (8H, m), 3.80(2H, s), 5.77(1H, q, J = 6.6 Hz),6.25-6.37(1H, m), 7.45-7.60(4H, m), 8.90-8.98(1H, m). MS (ESI) m/z 451(M + H)⁺. [α]_(b) = −33.4° (MeOH, _(c) = 0.815) 10

¹H-NMR (300 MHz, CDCl₃) δ = 1.35(3H, d, J = 6.6 Hz), 1.50-2.76(12H, m),3.80(2H, s), 5.97(1H, q, J = 6.3 Hz), 6.22-6.35(1H, m), 7.45-7.60(4H,m), 8.90-8.98(1H, m), MS (ESI) m/z 465 (M + H)⁺.

TABLE 6 Ex Structure Dat 11

¹H-NMR(300 MHz, CD₃OD) δ = 1.58(3H, d, J = 6.6 Hz), 2.80 (2H, t, J = 7.5Hz), 3.38(2H, t, J = 7.5 Hz), 4.52(2H, s), 6.16(1H, q, J = 6.6 Hz),7.22-7.75(8H, m), 8.87(1H, s). MS(ESI) m/z 493(M + H)⁺. 12

¹H-NMR(300 MHz, CD₃OD) δ = 1.52(3H, m), 2.81 (2H, t, J = 4.8 Hz),3.36(2H, t, J = 4.8 Hz), 4.53(2H, s), 6.08 (1H, m), 7.17(1H, m),7.35-7.78(8H, m), 8.87(1H, s). MS(ESI) m/z 537 (M + H)⁺., 539 (M + 2 +H)^(+.) 13

¹H-NMR(300 MHz, CD₃OD) δ = 1.32(3H, d, J = 6.3 Hz), 1.50-1.68(4H, m),2.05-2.12(2H, m), 2.28-2.39(2H, m), 2.81 (2H, t, J = 7.5 Hz), 3.37(2H,t, J = 7.5 Hz), 4.53(2H, s), 5.85(1H, brs), 7.43-7.78(4H, m), 8.87 (1H,s). MS(ESI) m/z 497(M + H)⁺. 14

¹H-NMR(300 MHz, CDCl₃) δ = 1.55(3H, d, J = 6.0 Hz), 2.95(4H, s),3.25(2H, s), 6.21(1H, q, J = 6.0 Hz), 6.67(1H, brs), 7.15-7.56 (8H, m),8.44(1H, brs), 8.86(1H, s). MS(ESI) m/z 461 (M + H)⁺. 15

¹H-NMR(300 MHz, CDCl₃) δ = 1.59(3H, d, J = 6.6 Hz), 2.66-3.01(8H, m),6.24(1H, q, J = 6.6 Hz), 6.53(1H, brs), 7.20-7.59 (8H, m), 8.89(1H, s).MS(ESI) m/z 475(M + H)⁺.

TABLE 7 Ex Structure Dat 16

¹H-NMR(300 MHz, CDCl₃) δ = 1.35(3H, d, J = 6.6 Hz), 1.87-1.98(2H, m),2.35-2.48(2H, m), 2.52-2.64 (2H, m), 2.93-3.03(4H, m), 3.27(2H, s),5.76(1H, q, J = 6.6 Hz), 6.36 (1H, brs), 7.36(2H, d, J = 7.5 Hz), 7.53(2H, d, J = 7.5 Hz), 8.92(1H, s). MS(ESI) m/z 451(M + H)⁺ 17

¹H-NMR(300 MHz, CDCl₃) δ = 1.34(3H, d, J = 6.6 Hz), 1.55-1.72(4H, m),2.05- 2.12(2H, m), 2.33-2.39(2H, m), 2.93- 3.03(4H, m), 3.28(2H, s),5.96(1H, q, J = 6.6 Hz), 6.31(1H, brs), 7.38 (2H, d, J = 7.8 Hz),7.54(2H, d, J = 7.8 Hz), 8.94(1H, s). MS(ESI) m/z 465 (M + H)⁺ 18

¹H-NMR(300 MHz, CDCl₃) δ = 1.54-1.62(3H, m), 2.56-2.65(2H, m),2.67-2.72(2H, m), 3.78(2H, s), 6.26(1H, q, J = 6.6 Hz), 6.48(1H, brs),7.22-7.68(8H, m), 8.72(1H, s). MS(ESI) m/z 461 (M + H)⁺. 19

¹H-NMR(300 MHz, DMSO-d₆) δ = 1.42-1.66(7H, m), 2.23(2H, t, J = 6.9 Hz),2.63(2H, t, J = 6.9 Hz), 5.90-6.02(1H, m), 7.20- 7.52(8H, m), 9.06(1H,s), 9.25-9.35(1H, m). MS(ESI) m/z 443 (M + H)⁺.

TABLE 8 Ex Structure Dat 20

¹H-NMR(300 MHz, CDCl₃) δ = 1.57(3H, d, J = 6.6 Hz), 2.53-2.67(2H, m),3.40-3.55(2H, m), 5.17(2H, s), 5.25-5.38(1H, m), 6.24(1H, q, J = 6.6Hz), 6.38-6.48(1H, m), 7.18-7.65(8H, m), 8.86-8.95(1H, m). MS(ESI) m/z488(M + H)⁺. 21

¹H-NMR(300 MHz, CDCl₃) δ = 1.54(3H, d, J = 6.3 Hz), 2.67-3.07(2H, m),4.43-4.60(1H, m), 6.12-6.25(1H, m), 6.78-6.88(1H, m), 7.15-7.67(8H, m),8.78-8.88(1H, m), 8.94(1H, s). MS(ESI) m/z 474 (M + H)⁺. 22

¹H-NMR(300 MHz, CDCl₃) δ = 1.58(3H, d, J = 6.3 Hz), 2.35(3H, s),6.24(1H, q, J = 6.3 Hz), 6.43(1H, brs), 7.20-7.68(8H, m), 8.90(1H, s).MS(ESI) m/z 401 (M + H)⁺. 23

¹H-NMR(300 MHz, CDCl₃) δ = 1.54(3H, d, J = 6.3 Hz), 2.67-3.07(2H, m),4.43-4.60(1H, m), 6.12-6.25(1H, m), 6.78-6.88(1H, m), 7.15-7.67(8H, m),8.78-8.88(1H, m), 8.94(1H, s). MS(ESI) m/z 359 (M + H)⁺. 24

¹H-NMR(300 MHz, CDCl₃) δ = 1.58(3H, d, J = 6.3 Hz), 1.77-1.95(4H, m),2.43-2.52(2H, m), 4.02-4.10(2H, m), 6.24(1H, q, J = 6.3 Hz),6.32-6.42(1H, m), 6.95-7.56(8H, m), 8.83-8.92(1H, m). MS(ESI) m/z459(M + H)⁺.

TABLE 9 Ex Structure Dat 25

¹H-NMR(300 MHz, DMSO-d₆) δ = 1.40-1.48(3H, m), 2.47-2.60(4H, m),5.88-5.97(1H, m), 7.20-7.80(8H, m), 9.00(1H, s), 9.24(1H, brs),10.12(1H, s). MS(ESI) m/z 458 (M + H)⁺. 26

¹H-NMR(300 MHz, DMSO-d₆) δ = 1.42-1.55 (3H, m), 2.04(3H, s),2.64-2.94(2H, m), 5.25-5.38(1H, m), 5.90-6.06(1H, m), 7.07-7.75(8H, m),9.06(1H, s), 9.25-9.38(1H, m), 10.32(1H, s). MS(ESI) m/z 516 (M + H)⁺.27

¹H-NMR(300 MHz, CDCl₃) δ = 1.55(3H, d, J = 6.0 Hz), 2.95(4H, s),3.25(2H, s), 6.21(1H, q, J = 6.0 Hz), 6.67(1H, brs), 7.15-7.56 (8H, m),8.44(1H, brs), 8.86(1H, s). MS(ESI) m/z 461 (M + H)⁺. [α]_(D) = −37.1°(_(c) = 2.15, MeOH) 28

¹H-NMR(300 MHz, CD₃OD) δ = 1.58(3H, d, J = 6.6 Hz), 2.80(2H, t, J = 7.5Hz), 3.38(2H, t, J = 7.5 Hz), 4.52(2H, s), 6.16(1H, q, J = 6.6 Hz),7.22-7.75(8H, m), 8.87(1H, s). MS(ESI) m/z 493 (M + H)⁺. 29

¹H-NMR(300 MHz, CDCl₃) δ = 1.59(3H, d, J = 6.6 Hz), 2.66-3.01(8H, m),6.24(1H, q, J = 6.6 Hz), 6.53(1H, brs), 7.20-7.59(8H, m), 8.89(1H, s).MS(ESI) m/z 475 (M + H)⁺. [α]_(D) = −42.7° (_(c) = 1.02, MeOH)

TABLE 10 Ex Structure Dat 30

¹H-NMR(300 MHz, CDCl₃) δ = 1.58(3H, d, J = 6.3 Hz), 2.58(4H, s),6.18-6.58(4H, m), 7.18-7.70(8H, m), 8.89(1H, s). MS(ESI) m/z 441(M +H)⁺. 31

¹H-NMR(300 MHz, CDCl₃) δ = 1.58 (3H, d, J = 6.9 Hz), 1.73(4H, m),2.41(2H, m), 2.73(2H, m), 6.24(1H, q, J = 6.6 Hz), 6.41(1H, bs),7.15-7.60(8H, m), 8.89(1H, s). Ms(ESI) m/z 443(M + H)⁺. 32

¹H-NMR(300 MHz, CDCl₃) δ = 1.00-1.78(9H, m), 2.34(2H, m), 2.69(2H, t, J= 7.5 Hz), 6.24(1H, t, J = 6.3 Hz), 7.20-7.58(8H, m), 8.89(1H, s).MS(ESI) m/z 457(M + H)⁺. 33

¹H-NMR(300 MHz, DMSO-d₆) δ = 1.03(6H, s), 1.40-1.62(5H, m), 2.18(2H, s),2.59(2H, m), 5.95(1H, m), 7.22-7.62(8H, m), 9.05(1H, s), 9.30(1H, bs).MS(ESI) m/z 471(M + H)⁺. 34

¹H-NMR(300 MHz, CDCl₃) δ = 0.853(2H, m), 1.19(8H, d, J = 6.9 Hz),1.57(3H, d, J = 6.3 Hz), 1.72(2H, m), 2.50(1H, q, J = 6.9 Hz), 2.69(2H,t, J = 6.9 Hz), 6.23(1H, q, J = 8.3 Hz), 6.46(1H, s), 6.89-7.56(8H, m),8.88(1H, s). MS(ESI) m/z 457(M + H)⁺.

TABLE 11 Compound No. IC₅₀ (nM) Compounds described Example 115 836 inWO 01/60819 Example 126 161 Compounds of Compound 2 51 the presentinvention Compound 3 22 Compound 4 65 Compound 5 74 Compound 6 22Compound 7 59 Compound 8 29 Compound 9 26 Compound 10 56 Compound 11 115Compound 12 68 Compound 13 104 Compound 14 146 Compound 15 44 Compound16 32 Compound 17 62 Compound 18 81 Compound 19 47 Compound 20 83Compound 21 84 Compound 22 140 Compound 23 116 Compound 24 131 Compound25 73 Compound 26 141 Compound 27 19 Compound 28 36 Compound 29 29Compound 30 107 Compound 31 76 Compound 32 114 Compound 33 119 Compound34 102

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that, within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

All patents and other references mentioned above are incorporated infull herein by this reference, the same as if set forth at length.

1. An azole compound represented by formula I:

wherein ring A is

R1 is any of a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstitutedcycloalkenyl group, a substituted or unsubstituted aryl group, asubstituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, a halogen atom, a substituted orunsubstituted alkoxy group, a substituted or unsubstituted aryloxygroup, a substituted or unsubstituted heteroaryloxy group, a substitutedor unsubstituted alkylthio group, a substituted or unsubstitutedarylthio group, a substituted or unsubstituted heteroarylthio group, asubstituted or unsubstituted alkylamino group, a substituted orunsubstituted dialkylamino group, a substituted or unsubstitutedcycloalkylamino group, a substituted or unsubstituted dicycloalkylaminogroup, a substituted or unsubstituted arylamino group, a substituted orunsubstituted heteroarylamino group, a substituted or unsubstitutedalkanoyl group, a substituted or unsubstituted carboxylic acid estergroup, a substituted or unsubstituted carbamoyl group, and an aminogroup optionally substituted by amino-protecting group(s); R2 is any ofa hydrogen atom, a substituted or unsubstituted lower alkyl group, asubstituted or unsubstituted aralkyl group, a substituted orunsubstituted aryl group, a substituted or unsubstituted heteroarylgroup, and a hydroxyl group; and R3 is any of a substituted orunsubstituted alkyl group, a substituted or unsubstituted cycloalkylgroup, a substituted or unsubstituted aryl group, a substituted orunsubstituted heteroaryl group, a substituted or unsubstitutedheterocyclic group, and a group represented by formula II:

wherein R4 is any of a substituted or unsubstituted alkyl group, asubstituted or unsubstituted cycloalkyl group, a substituted orunsubstituted cycloalkenyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, a halogen atom, a substituted orunsubstituted alkoxy group, a substituted or unsubstituted aryloxygroup, a substituted or unsubstituted heteroaryloxy group, a substitutedor unsubstituted alkylthio group, a substituted or unsubstitutedarylthio group, a substituted or unsubstituted heteroarylthio group, asubstituted or unsubstituted alkylamino group, a substituted orunsubstituted dialkylamino group, a substituted or unsubstitutedcycloalkylamino group, a substituted or unsubstituted dicycloalkylaminogroup, a substituted or unsubstituted arylamino group, a substituted orunsubstituted heteroarylamino group, and an amino group optionallysubstituted by amino-protecting group(s); and R5 and R6 may be the sameor different and each is any of a hydrogen atom, a substituted orunsubstituted lower alkyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, and a substituted or unsubstitutedaralkyl group, or R5 and R6 optionally form, together with the carbonatom bonded thereto, a 3- to 8-membered ring, or a pharmaceuticallyacceptable salt thereof.
 2. The azole compound of claim 1, wherein, informula I, R1 is any of a substituted or unsubstituted alkyl group, asubstituted or unsubstituted cycloalkyl group, a substituted orunsubstituted aryl group, a substituted or unsubstituted heteroarylgroup, a substituted or unsubstituted heterocyclic group, a substitutedor unsubstituted aralkyl group, a substituted or unsubstituted alkenylgroup, a substituted or unsubstituted alkynyl group, a halogen atom, asubstituted or unsubstituted alkoxy group, a substituted orunsubstituted aryloxy group, a substituted or unsubstitutedheteroaryloxy group, a substituted or unsubstituted alkylthio group, asubstituted or unsubstituted arylthio group, a substituted orunsubstituted heteroarylthio group, a substituted or unsubstitutedalkylamino group, a substituted or unsubstituted dialkylamino group, asubstituted or unsubstituted cycloalkylamino group, a substituted orunsubstituted dicycloalkylamino group, a substituted or unsubstitutedarylamino group, a substituted or unsubstituted heteroarylamino group, asubstituted or unsubstituted alkanoyl group, a substituted orunsubstituted carboxylic acid ester group, a substituted orunsubstituted carbamoyl group, and an amino group optionally substitutedby amino-protecting group(s); and R4 is any of a substituted orunsubstituted alkyl group, a substituted or unsubstituted cycloalkylgroup, a substituted or unsubstituted aryl group, a substituted orunsubstituted heteroaryl group, a substituted or unsubstitutedheterocyclic group, a substituted or unsubstituted aralkyl group, asubstituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, a halogen atom, a substituted orunsubstituted alkoxy group, a substituted or unsubstituted aryloxygroup, a substituted or unsubstituted heteroaryloxy group, a substitutedor unsubstituted alkylthio group, a substituted or unsubstitutedarylthio group, a substituted or unsubstituted heteroarylthio group, asubstituted or unsubstituted alkylamino group, a substituted orunsubstituted dialkylamino group, a substituted or unsubstitutedcycloalkylamino group, a substituted or unsubstituted dicycloalkylaminogroup, a substituted or unsubstituted arylamino group, a substituted orunsubstituted heteroarylamino group, and an amino group optionallysubstituted by amino-protecting group(s), or a pharmaceuticallyacceptable salt thereof.
 3. The azole compound of claim 1, wherein, informula I, R2 is any of a hydrogen atom, a substituted or unsubstitutedlower alkyl group, a substituted or unsubstituted aralkyl group, and ahydroxyl group; and R3 is a group represented by the following formulaII:

wherein R4 is any of a substituted or unsubstituted alkyl group, asubstituted or unsubstituted cycloalkyl group, a substituted orunsubstituted cycloalkenyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, a halogen atom, a substituted orunsubstituted alkoxy group, a substituted or unsubstituted aryloxygroup, a substituted or unsubstituted heteroaryloxy group, a substitutedor unsubstituted alkylthio group, a substituted or unsubstitutedarylthio group, a substituted or unsubstituted heteroarylthio group, asubstituted or unsubstituted alkylamino group, a substituted orunsubstituted dialkylamino group, a substituted or unsubstitutedarylamino group, a substituted or unsubstituted heteroarylamino group,and an amino group optionally substituted by amino-protecting group(s);and R5 and R6 may be the same or different and each is any of a hydrogenatom and a substituted or unsubstituted lower alkyl group, or R5 and R6optionally form, together with the carbon atom bonded thereto, a 3- to8-membered ring, or a pharmaceutically acceptable salt thereof.
 4. Theazole compound of claim 3, wherein, in formula I, R1 is any of asubstituted or unsubstituted alkyl group, a substituted or unsubstitutedcycloalkyl group, a substituted or unsubstituted aryl group, asubstituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, a halogen atom, a substituted orunsubstituted alkoxy group, a substituted or unsubstituted aryloxygroup, a substituted or unsubstituted heteroaryloxy group, a substitutedor unsubstituted alkylthio group, a substituted or unsubstitutedarylthio group, a substituted or unsubstituted heteroarylthio group, asubstituted or unsubstituted alkylamino group, a substituted orunsubstituted dialkylamino group, a substituted or unsubstitutedcycloalkylamino group, a substituted or unsubstituted dicycloalkylaminogroup, a substituted or unsubstituted arylamino group, a substituted orunsubstituted heteroarylamino group, a substituted or unsubstitutedalkanoyl group, a substituted or unsubstituted carboxylic acid estergroup, a substituted or unsubstituted carbamoyl group, and an aminogroup optionally substituted by amino-protecting group(s); and R4 is anyof a substituted or unsubstituted alkyl group, a substituted orunsubstituted cycloalkyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, a halogen atom, a substituted orunsubstituted alkoxy group, a substituted or unsubstituted aryloxygroup, a substituted or unsubstituted heteroaryloxy group, a substitutedor unsubstituted alkylthio group, a substituted or unsubstitutedarylthio group, a substituted or unsubstituted heteroarylthio group, asubstituted or unsubstituted alkylamino group, a substituted orunsubstituted dialkylamino group, a substituted or unsubstitutedarylamino group, a substituted or unsubstituted heteroarylamino group,and an amino group optionally substituted by amino-protecting group(s),or a pharmaceutically acceptable salt thereof.
 5. The azole compound ofclaim 3, wherein, in formula I, the substituent of the group for R1 isany of a cyano group and a group represented by the following formulaIII:Z-Y-X-  formula III wherein X and Y may be the same or different andeach is any of a substituted or unsubstituted lower alkylene group, asubstituted or unsubstituted lower alkenylene group, a substituted orunsubstituted lower alkynylene group, a substituted or unsubstitutedcycloalkylene group, a substituted or unsubstituted arylene group, asubstituted or unsubstituted heteroarylene group, a substituted orunsubstituted heterocyclylene group, a carbonyl group, an oxygen atom,an sulfur atom, a sulfinyl group, a sulfonyl group, a substituted orunsubstituted amino group, and a bond, and Z is any of a substituted orunsubstituted lower alkyl group, a substituted or unsubstituted loweralkenyl group, a substituted or unsubstituted lower alkynyl group, asubstituted or unsubstituted alkanoyl group, a substituted orunsubstituted aryl group, a substituted or unsubstituted heteroarylgroup, a substituted or unsubstituted heterocyclic group, a substitutedor unsubstituted alkoxy group, a substituted or unsubstituted aryloxygroup, a substituted or unsubstituted heteroaryloxy group, a substitutedor unsubstituted alkylthio group, a substituted or unsubstitutedarylthio group, a substituted or unsubstituted heteroarylthio group, asubstituted or unsubstituted alkylamino group, a substituted orunsubstituted dialkylamino group, a substituted or unsubstitutedcycloalkylamino group, a substituted or unsubstituted dicycloalkylaminogroup, a substituted or unsubstituted arylamino group, a substituted orunsubstituted heteroarylamino group, and a substituted or unsubstitutedcarbamoyl group, wherein the substituent of the group for Z is any of acarboxyl group, a carboxylic acid ester group, a substituted orunsubstituted carbamoyl group, a cyano group, a hydroxyl group, asulfonic acid group, a sulfonamido group, a phosphoric acid group,phosphoric acid monoester group, phosphoric acid diester group, an aminogroup optionally substituted by amino-protecting group(s), a thiolgroup, a halogen atom, a substituted or unsubstituted aryl group, asubstituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstitutedalkanoyl group, a substituted or unsubstituted arylcarbonyl group, and asubstituted or unsubstituted heteroarylcarbonyl group, and the group forZ optionally has multiple substituents described above that may be thesame or different; R2 is any of a hydrogen atom, a substituted orunsubstituted lower alkyl group, and a substituted or unsubstitutedaralkyl group; R4 is any of a substituted or unsubstituted alkyl group,a substituted or unsubstituted cycloalkyl group, a substituted orunsubstituted cycloalkenyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, and a halogen atom; and R5 and R6 may bethe same or different and each is any of a hydrogen atom and asubstituted or unsubstituted lower alkyl group, or a pharmaceuticallyacceptable salt thereof.
 6. The azole compound of claim 3, wherein, informula I, the substituent of the group for R1 is any of a hydroxylgroup and a group represented by the following formula III:Z-Y-X-  formula III wherein X is any of an oxygen atom, a substituted orunsubstituted amino group, a sulfur atom, and a bond, Y is any of acarbonyl group, a sulfonyl group, and a bond, and Z is any of asubstituted or unsubstituted alkyl group, a substituted or unsubstitutedalkenyl group, a substituted or unsubstituted alkynyl group, asubstituted or unsubstituted alkanoyl group, a substituted orunsubstituted aryl group, a substituted or unsubstituted heteroarylgroup, a substituted or unsubstituted heterocyclic group, a substitutedor unsubstituted alkoxy group, a substituted or unsubstituted aryloxygroup, a substituted or unsubstituted heteroaryloxy group, a substitutedor unsubstituted alkylthio group, a substituted or unsubstitutedarylthio group, a substituted or unsubstituted heteroarylthio group, asubstituted or unsubstituted alkylamino group, a substituted orunsubstituted dialkylamino group, a substituted or unsubstitutedcycloalkylamino group, a substituted or unsubstituted dicycloalkylaminogroup, a substituted or unsubstituted arylamino group, and a substitutedor unsubstituted heteroarylamino group, wherein the substituent of thegroup for Z is any of a lower alkyl group, a carboxyl group, acarboxylic acid ester group, a substituted or unsubstituted alkanoyloxygroup, a substituted or unsubstituted carbamoyl group, a cyano group, ahydroxyl group, a sulfonic acid group, a sulfonamido group, a phosphoricacid group, a phosphoric acid monoester group, a phosphoric acid diestergroup, an amino group optionally substituted by amino-protectinggroup(s), a thiol group, a halogen atom, a substituted or unsubstitutedaryl group, a substituted or unsubstituted heteroaryl group, asubstituted or unsubstituted heterocyclic group, a substituted orunsubstituted alkanoyl group, a substituted or unsubstitutedarylcarbonyl group, and a substituted or unsubstitutedheteroarylcarbonyl group, and the group for Z optionally has multiplesubstituents described above that may be the same or different; R2 isany of a hydrogen atom, a substituted or unsubstituted lower alkylgroup, and a substituted or unsubstituted aralkyl group; R4 is any of asubstituted or unsubstituted alkyl group, a substituted or unsubstitutedcycloalkyl group, a substituted or unsubstituted cycloalkenyl group, asubstituted or unsubstituted aryl group, a substituted or unsubstitutedheteroaryl group, a substituted or unsubstituted heterocyclic group, asubstituted or unsubstituted aralkyl group, a substituted orunsubstituted alkenyl group, a substituted or unsubstituted alkynylgroup, and a halogen atom; and R5 and R6 may be the same or differentand each is any of a hydrogen atom and a substituted or unsubstitutedlower alkyl group, or a pharmaceutically acceptable salt thereof.
 7. Theazole compound of claim 5, wherein, in formula I, R1 is any of asubstituted or unsubstituted allyl group, a substituted or unsubstitutedcycloalkyl group, a substituted or unsubstituted aryl group, asubstituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, a halogen atom, a substituted orunsubstituted alkoxy group, a substituted or unsubstituted aryloxygroup, a substituted or unsubstituted heteroaryloxy group, a substitutedor unsubstituted alkylthio group, a substituted or unsubstitutedarylthio group, a substituted or unsubstituted heteroarylthio group, asubstituted or unsubstituted alkylamino group, a substituted orunsubstituted dialkylamino group, a substituted or unsubstitutedcycloalkylamino group, a substituted or unsubstituted dicycloalkylaminogroup, a substituted or unsubstituted arylamino group, a substituted orunsubstituted heteroarylamino group, a substituted or unsubstitutedalkanoyl group, a substituted or unsubstituted carboxylic acid estergroup, a substituted or unsubstituted carbamoyl group, and an aminogroup optionally substituted by amino-protecting group(s); and R4 is anyof a substituted or unsubstituted alkyl group, a substituted orunsubstituted cycloalkyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, and a halogen atom, or a pharmaceuticallyacceptable salt thereof.
 8. The azole compound of claim 5, wherein, informula I, R1 is any of a substituted or unsubstituted alkyl group, asubstituted or unsubstituted cycloalkyl group, a substituted orunsubstituted aryl group, a substituted or unsubstituted heteroarylgroup, a substituted or unsubstituted heterocyclic group, and asubstituted or unsubstituted aralkyl group, or a pharmaceuticallyacceptable salt thereof.
 9. The azole compound of claim 2, wherein, informula I, R1 is a substituted phenyl group, wherein the substituent ofthe group for R1 is any of a cyano group and a group represented by thefollowing formula III:Z-Y-X-  formula III wherein X is any of a methylene group and a ethylenegroup, Y is any of a sulfur atom, a sulfinyl group, a sulfonyl group, anoxygen atom, a substituted or unsubstituted amino group, and a methylenegroup, and Z is any of a substituted or unsubstituted lower alkyl group,a substituted or unsubstituted lower alkenyl group, a substituted orunsubstituted alkanoyl group, a substituted or unsubstituted triazolegroup, and a substituted or unsubstituted tetrazole group, wherein thesubstituent of the group for Z is any of a carboxyl group, analkoxycarbonyl group, a furyl group, a phenyl group, a hydroxyl group, acarbamoyl group, a carbamoyl group substituted by lower alkyl group(s),a carbamoyl group substituted by carboxy lower alkyl group(s), acarbamoyl group substituted by lower alkyl group(s) substituted by afuryl group, an amino group optionally substituted by amino-protectinggroup(s), a sulfonic acid group, a pyrrolylcarbonyl group, a pyridylgroup, and a halogen atom, and the group for Z optionally has multiplesubstituents described above that may be the same or different; R2 is ahydrogen atom; and R3 is a group represented by the following formulaII:

wherein R4 is a substituted or unsubstituted phenyl group wherein thesubstituent of the group for R4 is a halogen atom, R5 is any of ahydrogen atom, a lower alkyl group, and a lower alkyl group substitutedby 1 to 3 halogen atoms, and R6 is a hydrogen atom, or apharmaceutically acceptable salt thereof.
 10. The azole compound ofclaim 6, wherein, in formula I, R1 is any of a substituted orunsubstituted phenyl group, a substituted or unsubstituted heteroarylgroup, a substituted or unsubstituted heterocyclic group, a substitutedor unsubstituted cycloalkyl group, and a substituted or unsubstitutedcycloalkenyl group wherein the substituent of the group for R1 is any ofa hydroxyl group and a group represented by the following formula III:Z-Y-X-  formula III wherein X is any of an oxygen atom, a substituted orunsubstituted amino group, a sulfur atom, and a bond, Y is any of acarbonyl group, a sulfonyl group, and a bond, and Z is a substituted orunsubstituted alkyl group, wherein the substituent of the group for Z isany of a lower alkyl group, a carboxyl group, a carboxylic acid estergroup, a substituted or unsubstituted alkanoyloxy group, a substitutedor unsubstituted carbamoyl group, a cyano group, a hydroxyl group, asulfonic acid group, a sulfonamido group, a phosphoric acid group, aphosphoric acid monoester group, a phosphoric acid diester group, anamino group optionally substituted by amino-protecting group(s), a thiolgroup, a halogen atom, a substituted or unsubstituted aryl group, asubstituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstitutedalkanoyl group, a substituted or unsubstituted arylcarbonyl group, and asubstituted or unsubstituted heteroarylcarbonyl group, and the group forZ optionally has multiple substituents described above that may be thesame or different, or a pharmaceutically acceptable salt thereof. 11.The azole compound of claim 5, wherein, in formula I, R1 is any of asubstituted or unsubstituted aryl group, a substituted or unsubstitutedheteroaryl group, a substituted or unsubstituted heterocyclic group, asubstituted or unsubstituted cycloalkyl group, and a substituted orunsubstituted cycloalkenyl group, wherein the substituent of the groupfor R1 is a group represented by the following formula III:Z-Y-X-  formula III wherein each symbol is as defined in claim 5; R2 isa hydrogen atom; R4 is any of a substituted or unsubstituted aryl group,a substituted or unsubstituted heteroaryl group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstitutedcycloalkyl group, and a substituted or unsubstituted cycloalkenyl group;R5 is a substituted or unsubstituted lower alkyl group; and R6 is ahydrogen atom, or a pharmaceutically acceptable salt thereof.
 12. Theazole compound of claim 11, wherein, in formula I, R4 is a substitutedor unsubstituted cycloalkenyl group, or a pharmaceutically acceptablesalt thereof.
 13. The azole compound of claim 10, wherein, in formula I,R1 is a substituted phenyl group, wherein the substituent of the groupfor R1 is any of a hydroxyl group and a group represented by thefollowing formula III:Z-Y-X-  formula III wherein X is any of an oxygen atom and a substitutedor unsubstituted amino group, Y is any of a carbonyl group and a bond,and Z is a substituted or unsubstituted alkyl group wherein thesubstituent of the group for Z is any of a lower alkyl group, a carboxylgroup, a carboxylic acid ester group, a substituted or unsubstitutedalkanoyloxy group, a substituted or unsubstituted carbamoyl group, acyano group, a hydroxyl group, a sulfonic acid group, a sulfonamidogroup, a phosphoric acid group, a phosphoric acid monoester group, aphosphoric acid diester group, an amino group optionally substituted byamino-protecting group(s), a thiol group, a halogen atom, a substitutedor unsubstituted aryl group, a substituted or unsubstituted heteroarylgroup, a substituted or unsubstituted heterocyclic group, a substitutedor unsubstituted alkanoyl group, a substituted or unsubstitutedarylcarbonyl group, and a substituted or unsubstitutedheteroarylcarbonyl group, and the group for Z optionally has multiplesubstituents described above that may be the same or different, or apharmaceutically acceptable salt thereof.
 14. The azole compound ofclaim 11, wherein, in formula I, R1 is a substituted phenyl group; X isany of a substituted or unsubstituted methylene group, a substituted orunsubstituted ethylene group, and a substituted or unsubstitutedvinylene group; Y is any of a sulfur atom, a sulfonyl group, asubstituted or unsubstituted methylene group, and an oxygen atom; Z isany of a substituted methyl group, a substituted ethyl group, asubstituted propyl group, and a substituted carbamoyl group, wherein thesubstituent of the group for Z is any of a carboxyl group, a carboxylicacid ester group, an acetylamino group, a sulfonic acid group, and ahydroxyl group, and the group for Z optionally has multiple substituentsdescribed above that may be the same or different; R4 is any of asubstituted phenyl group, a substituted cyclopentenyl group, asubstituted cyclohexenyl group, and a substituted thienyl group, whereinthe substituent of the group for R4 is any of a chlorine atom, a bromineatom, and a substituted or unsubstituted lower alkyl group; and R5 is amethyl group, or a pharmaceutically acceptable salt thereof.
 15. Theazole compound of claim 13, wherein, in formula I, the substituent ofthe group for R1 is any of a hydroxyl group and a group represented bythe following formula III:Z-Y-X-  formula III wherein X is any of an oxygen atom and a substitutedor unsubstituted amino group, Y is any of a carbonyl group and a bond,and Z is a substituted or unsubstituted alkyl group, wherein thesubstituent of the group for Z is any of a lower alkyl group, a carboxylgroup, a carboxylic acid ester group, an alkanoyloxy group, a hydroxylgroup, a sulfonic acid group, and an amino group optionally substitutedby amino-protecting group(s), and the group for Z optionally hasmultiple substituents described above that may be the same or different,or a pharmaceutically acceptable salt thereof.
 16. The azole compound ofclaim 14, wherein, in formula I, X is any of a methylene group, aethylene group, and a vinylene group; Y is any of a sulfur atom, asulfonyl group, a methylene group, and an oxygen atom; Z is any of asubstituted methyl group, a substituted ethyl group, a substitutedpropyl group, and a substituted carbamoyl group, wherein the substituentof the group for Z is any of a carboxyl group, a carboxylic acid estergroup, an acetylamino group, and a sulfonic acid group, and the groupfor Z optionally has multiple substituents described above that may bethe same or different; and R4 is any of a substituted phenyl group, asubstituted cyclopentenyl group, and a substituted cyclohexenyl group,wherein the substituent of the group for R4 is any of a chlorine atomand a bromine atom, or a pharmaceutically acceptable salt thereof.
 17. Apharmaceutical composition, comprising a compound according to claim 1or a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 18. A method of inhibiting the physiologicalactivity of LPA, which comprises administering an effective amount of acompound according to claim 1 or a pharmaceutically acceptable saltthereof to a mammal in need thereof.
 19. A method for the prophylaxis ortreatment of hepatic disease, which comprises administering an effectiveamount of a compound according to claim 1 or a pharmaceuticallyacceptable salt thereof to a mammal in need thereof.
 20. A method forthe prophylaxis or treatment of organ fibrosis, which comprisesadministering an effective amount of a compound according to claim 1 ora pharmaceutically acceptable salt thereof to a mammal in need thereof.21. A method of improving liver function, which comprises administeringan effective amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof to a mammal in need thereof.22. A package, comprising a pharmaceutical composition according toclaim 17 and written matter, wherein said written matter states thatsaid pharmaceutical composition can or should be used for inhibiting thephysiological activity of LPA.
 23. A package, comprising apharmaceutical composition according to claim 17 and written matter,wherein said written matter states that said pharmaceutical compositioncan or should be used for the prophylaxis or treatment of liver disease.24. A package, comprising a pharmaceutical composition according toclaim 17 and written matter, wherein said written matter states thatsaid pharmaceutical composition can or should be used for theprophylaxis or treatment of organ fibrosis.
 25. A package, comprising apharmaceutical composition according to claim 17 and written matter,wherein said written matter states that said pharmaceutical compositioncan or should be used for improving liver function